Aromatic amides

ABSTRACT

This application relates to a compound of formula I (or a pharmaceutically acceptable salt thereof) as defined herein, pharmaceutical compositions thereof, and its use as an inhibitor of factor Xa, as well as a process for its preparation and intermediates therefor.

This application is a 371 of PCT/US99/29946, filed Dec. 15, 1999 andclaims the benefit of U.S. Provisional Application No. 60/113,556, filedDec. 23, 1998.

This invention relates to antithrombotic aromatic amides whichdemonstrate activity as inhibitors of factor Xa and, accordingly, whichare useful anticoagulants in mammals. In particular it relates toaromatic amides having high anticoagulant activity, and antithromboticactivity. Thus, this invention relates to new amides which areinhibitors of factor Xa, pharmaceutical compositions containing theamides as active ingredients, and the use of the amides asanticoagulants for prophylaxis and treatment of thromboembolic disorderssuch as venous thrombosis, pulmonary embolism, arterial thrombosis, inparticular myocardial ischemia, myocardial infarction and cerebralthrombosis, general hypercoagulable states and local hypercoagulablestates, such as following angioplasty and coronary bypass operations,and generalized tissue injury as it relates to the inflammatory process.In addition, the antithrombotic agents are useful as anticoagulants inin vitro applications.

The process of blood coagulation, thrombosis, is triggered by a complexproteolytic cascade leading to the formation of thrombin. Thrombinproteolytically removes activation peptides from the Aα-chains and theBβ-chains of fibrinogen, which is soluble in blood plasma, initiatinginsoluble fibrin formation. The formation of thrombin from prothrombinis catalyzed by factor Xa.

Anticoagulation currently is achieved by the administration of heparinsand coumarins. Parenteral pharmacological control of coagulation andthrombosis is based on inhibition of thrombin through the use ofheparins. Heparins act indirectly on thrombin by accelerating theinhibitory effect of endogenous antithrombin III (the main physiologicalinhibitor of thrombin). Because antithrombin III levels vary in plasmaand because clot-bound thrombin seems resistant to this indirectmechanism, heparins can be an ineffective treatment. Because coagulationassays are believed to be associated with efficacy and with safety,heparin levels must be monitored with coagulation assays (particularlythe activated partial thromboplastin time (APTT) assay). Coumarinsimpede the generation of thrombin by blocking the posttranslationalgamma-carboxylation in the synthesis of prothrombin and other proteinsof this type. Because of their mechanism of action, the effect ofcoumarins can only develop slowly, 6-24 hours after administration.Further, they are not selective anticoagulants. Coumarins also requiremonitoring with coagulation assays (particularly the prothrombin time(PT) assay).

Recently, interest has grown in small synthetic molecules whichdemonstrate potent direct inhibition of thrombin and factor Xa. See,Joseph P. Vacca (Annette M. Doherty Section Editor), Annual Reports inMedicinal Chemistry, (1998), 33, 81-90.

Although the heparins and coumarins are effective anticoagulants, therestill exists a need for anticoagulants which act selectively on factorXa or thrombin, and which, independent of antithrombin III, exertinhibitory action shortly after administration, preferably by an oralroute, and do not interfere with lysis of blood clots, as required tomaintain hemostasis.

The present invention is directed to the discovery that the amides ofthe present invention, as defined below, are potent inhibitors of factorXa which may have high bioavailability following oral administration.

According to the invention there is provided a compound of formula I

(or a pharmaceutically acceptable salt thereof) wherein:

A³, A⁴, A⁵ and A⁶, together with the two carbons to which they areattached, complete a substituted benzene in which A³ is CR³, A⁴ is CR⁴,A⁵ is CR⁵, and A⁶ is CR⁶ wherein

R³ is hydrogen, methyl, methoxy, fluoro, chloro or carboxy;

one of R⁴ and R⁵ is hydrogen, (1-4C)alkyl, halo, trifluoromethyl,trifluoromethoxy, R^(f)O—, R^(f)O₂CCH₂O—, HO(CH₂)_(a)— (in which a is 2,3 or 4), R^(f)O₂C—, R^(f)O₂CCH₂—, R^(g)NH—, R^(h)SO₂—, hydroxymethyl,formyl, cyano, acetyl, 1-hydroxyethyl, 1-(hydroxyimino)ethyl,1-(methoxyimino)ethyl, methylthio or R^(f)O₂C(CH₂)₂—;

the other of R⁴ and R⁵ is hydrogen; and

R⁶ is hydrogen, methyl, fluoro, chloro or methoxy;

in which R^(f) is hydrogen, (1-4C)alkyl or benzyl; R^(g) is hydrogen orR^(h)SO₂—; and R^(h) is (1-4C)alkyl or dimethylamino;

or each of R³, R⁴ and R⁶ is hydrogen; and R⁵ is vinyl, 2-cyanovinyl,2-({(1-2C)alkoxy}carbonyl)vinyl or R^(a) in which R^(a) is phenyl (whichis unsubstituted or bears one or more substituents independentlyselected from halo, methyl, methoxy and hydroxy) or heteroaryl (whichheteroaryl is a 5-membered aromatic ring which includes one to fourheteroatoms selected from sulfur, oxygen and nitrogen or is a 6-memberedaromatic ring which includes one to three nitrogen atoms, wherein theheteroaryl is attached at carbon and may bear one or more methylsubstituents on carbon or nitrogen);

L¹ is —CO—NH— such that —L¹—Q¹ is —CO—NH—Q¹;

Q¹ is 2-pyridinyl (which bears a methyl, methoxy, methylthio, fluoro orchloro substituent at the 5-position), 3-pyridinyl (which bears amethyl, fluoro or chloro substituent at the 6-position), 2-pyrimidinyl(which may bear a methyl, fluoro or chloro substituent at the5-position) or 3-pyridazinyl (which may bear a methyl, fluoro or chlorosubstituent at the 6-position);

R² is —L²—Q² in which —L²— is —NH—CO—, —NH—CO—X—, —NH—CO—O—X—,—NH—CO—NH—X—, —NH—CH₂—, —NH—C(CH₃)—, —N(CH₃)—CH₂— or —O—CH₂—; and Q² isQ^(2A), Q^(2B), Q^(2C), Q^(2D), Q^(2E) or Q^(2F) wherein X is a singlebond or methylene and the values of L² and Q² are together selected from—NH—CO—X—Q^(2A), —NH—CO—O—X—Q^(2A), —NH—CO—NH—X—Q^(2A), —NH—CH₂—Q^(2A),—NH—C(CH₃)H—Q^(2A), —N(CH₃)—CH₂—Q^(2A), —O—CH₂—Q^(2A), —NH—CO—X—Q^(2B),—NH—CO—Q^(2C), —NH—CO—Q^(2D), —NH—CO—Q^(2E) and —NH—CO—Q^(2F) in which:

Q^(2A) (showing the L² to which it is attached) is

 in which

each of m and n independently is 0 or 1, or m is 2 and n is 1, and

R^(2A) is hydrogen, t-butyl, methylsulfonyl, —CHR^(y)R^(z),—CHR^(w)R^(x), or 4-pyridinyl (which is unsubstituted or bears asubstituent R^(v) at the 2- or 3-position) wherein

R^(v) is methyl, hydroxymethyl, {(1-2C)alkoxy}carbonyl; cyano,carbamoyl, thiocarbamoyl, or N-hydroxyamidino;

each of R^(w) and R^(x) independently is hydrogen or (1-3C)normal alkyl;or —CHR^(w)R^(x) is 2-indanyl or (showing the nitrogen to which it isattached) is

in which T is a single bond or methylene and U is methylene, ethylene,oxy, —S(O)_(q)— (wherein q is 0, 1 or 2) or imino (which may bear amethyl substituent), or T is ethan-1,1-diyl and U is a single bond ormethylene;

R^(y) is hydrogen or methyl; and

R^(z) is isopropyl, t-butyl, (3-6C)cycloalkyl, phenyl (which isunsubstituted or bears one or more substituents independently selectedfrom halo, methyl, methoxy and hydroxy), 4-quinolinyl or heteroaryl(which heteroaryl is a 5-membered aromatic ring which includes one tofour heteroatoms selected from sulfur, oxygen and nitrogen or is a6-membered aromatic ring which includes one to three nitrogen atoms,wherein the heteroaryl is attached at carbon and may bear one or moremethyl substituents on carbon or nitrogen);

or R^(2A) is —L^(b)—CH₂—R^(b) in which —L^(b)— is a direct bond, —CH₂—,—C(CH₃)H— or —CH₂—CH₂—; and R^(b) is carboxy, {(1-2C) alkoxy}carbonyl,cyano, carbamoyl or trifluoromethyl;

or R^(2A) is —CO—R^(c) in which R^(c) is hydrogen, (1-3C)alkyl,{(1-2C)alkoxy}carbonyl-(CH₂)_(c)— (in which c is 1 or 2), phenyl (whichis unsubstituted or bears one or more substituents independentlyselected from halo, methyl, methoxy and hydroxy), heteroaryl (whichheteroaryl is a 5-membered aromatic ring which includes one to fourheteroatoms selected from sulfur, oxygen and nitrogen or is a 6-memberedaromatic ring which includes one to three nitrogen atoms, wherein theheteroaryl is attached at carbon and may bear one or more methylsubstituents on carbon or nitrogen) or —NR^(d)R^(e) in which each ofR^(d) and R^(e) is independently hydrogen, methyl or ethyl, or—NR^(d)R^(e) is pyrrolidino, piperidino, morpholino or thiomorpholino;

Q^(2B) is 1-piperazinyl which bears at the 4-position the group R^(2A)(defined as above);

Q^(2C) is 3,4-didehydropiperidin-4-yl which bears at the 1-position thegroup R^(2A) (defined as above);

Q^(2D) is cyclohexyl which bears at the 4-position the group—NR^(s)R^(t) in which each of R^(s) and R^(t) independently is hydrogenor methyl or R^(s) and R^(t) together are trimethylene ortetramethylene;

Q^(2E) is 1-piperidinyl which bears at the 4-position the group—NR^(s)R^(t) (defined as above); and

Q^(2F) (showing the L² to which it is attached) is

 in which R^(o) is hydrogen, halo, (1-6C)alkyl, hydroxy, (1-4C)alkoxy,benzyloxy or (1-4C)alkylthio; and R^(p) is acetylamino, 1-hydroxyethyl,1-hydroxy-1-methylethyl, 1-methoxy-1-methylethyl, 4-piperidinyl,4-pyridinyl, dimethylaminosulfonyl or —J—R^(q) in which J is a singlebond, methylene, carbonyl, oxy, —S(O)_(q)— (wherein q is 0, 1 or 2), or—NR^(r)— (wherein R^(r) is hydrogen or methyl); and R^(q) is(1-6C)alkyl, phenyl, 3-pyridyl or 4-pyridyl; or —NR^(q)R^(r) ispyrrolidino.

A particular compound of formula I is one wherein:

A³, A⁴, A⁵ and A⁶, together with the two carbons to which they areattached, complete a substituted benzene in which A³ is CR³, A⁴ is CR⁴,A⁵ is CR⁵, and A⁶ is CR⁶; wherein

R³ is hydrogen, methyl, fluoro, chloro or carboxy;

one of R⁴ and R⁵ is hydrogen, (1-4C)alkyl, halo, trifluoromethyl,trifluoromethoxy, R^(f)O—, R^(f)O₂CCH₂O—, HO(CH₂)_(a)— (in which a is 2,3 or 4), R^(f)O₂C—, R^(f)O₂CCH₂—, R^(g)NH— or R^(h)SO₂—;

the other of R⁴ and R⁵ is hydrogen; and

R⁶ is hydrogen, methyl, fluoro, chloro or methoxy;

in which R^(f) is hydrogen, (1-4C)alkyl or benzyl; R^(g) is hydrogen orR^(h)SO₂—; and R^(h) is (1-4C)alkyl or dimethylamino;

L¹ is —CO—NH— such that —L¹Q¹ is —CO—NH—Q¹;

Q¹ is 2-pyridinyl (which bears a methyl, methoxy, methylthio, fluoro orchloro substituent at the 5-position), 3-pyridinyl (which bears amethyl, fluoro or chloro substituent at the 6-position), 2-pyrimidinyl(which may bear a methyl, fluoro or chloro substituent at the5-position) or 3-pyridazinyl (which may bear a methyl, fluoro or chlorosubstituent at the 6-position);

R² is —L²—Q² in which —L²— is —NH—CO—, —NH—CO—X—, —NH—CO—O—X—,—NH—CO—NH—X—, —NH—CH₂— or —O—CH₂—; and Q² is Q^(2A), Q^(2B), Q^(2C),Q^(2D), Q^(2E) or Q^(2F) wherein X is a single bond or methylene and thevalues of L² and Q² are together selected from —NH—CO—X—Q^(2A),—NH—CO—O—X—Q^(2A), —NH—CO—NH—X—Q_(2A), —NH—CH₂—Q^(2A), —O—CH₂—Q^(2A),—NH—CO—X—Q^(2B), —NH—CO—Q^(2C), —NH—CO—O^(2D), —NH—CO—Q^(2E) and—NH—CO—O^(2F) in which:

Q^(2A) (showing the L² to which it is attached) is

 in which

each of m and n independently is 0 or 1, and

R^(2A) is hydrogen, t-butyl, methylsulfonyl, —CHR^(y)R^(z),—CHR^(w)R^(x), or 4-pyridinyl (which is unsubstituted or bears asubstituent R^(v) at the 2- or 3-position) wherein

R^(v) is methyl, hydroxymethyl, {(1-2C)alkoxy}carbonyl; cyano,carbamoyl, thiocarbamoyl, or N-hydroxyamidino;

each of R^(w) and R^(x) independently is hydrogen or (1-3C)normal alkyl;or —CHR^(w)R^(x) is 2-indanyl or (showing the nitrogen to which it isattached) is

 in which T is a single bond or methylene and U is methylene, ethylene,oxy, —S(O)_(q)— (wherein q is 0, 1 or 2) or imino (which may bear amethyl substituent), or T is ethan-1,1-diyl and U is a single bond ormethylene;

R^(y) is hydrogen or methyl; and

R^(z) is isopropyl, t-butyl, (3-6C)cycloalkyl, phenyl (which isunsubstituted or bears one or more substituents independently selectedfrom halo, methyl, methoxy and hydroxy), 4-quinolinyl or heteroaryl(which heteroaryl is a 5-membered aromatic ring which includes one tofour heteroatoms selected from sulfur, oxygen and nitrogen or is a6-membered aromatic ring which includes one to three nitrogen atoms,wherein the heteroaryl is attached at carbon and may bear one or moremethyl substituents on carbon or nitrogen);

Q^(2B) is 1-piperazinyl which bears at the 4-position the group R^(2A)(defined as above);

Q^(2C) is 3,4-didehydropiperidin-4-yl which bears at the 1-position thegroup R^(2A) (defined as above);

Q^(2D) is cyclohexyl which bears at the 4-position the group—NR^(s)R^(t) in which each of R^(s) and R^(t) independently is hydrogenor methyl or R^(s) and R^(t) together are trimethylene ortetramethylene;

Q^(2E) is 1-piperidinyl which bears at the 4-position the group—NR^(s)R^(t) (defined as above); and

Q^(2F) (showing the L² to which it is attached) is

 in which R^(o) is hydrogen, halo, (1-6C)alkyl, hydroxy, (1-4C)alkoxy,benzyloxy or (1-4C)alkylthio; and R^(p) is acetylamino, 1-hydroxyethyl,1-hydroxy-1-methylethyl, 1-methoxy-1-methylethyl, 4-piperidinyl,4-pyridinyl, dimethylaminosulfonyl or —J—R^(q) in which J is a singlebond, methylene, carbonyl, oxy, —S(O)_(q)— (wherein q is 0, 1 or 2), or—NR^(r)— (wherein R^(r) is hydrogen or methyl); and R^(q) is(1-6C)alkyl, phenyl, 3-pyridyl or 4-pyridyl.

As used herein, the expression a compound of formula I or the expressiona compound of the invention includes the compound and any conventionalprodrug thereof, as well as a pharmaceutically acceptable salt of saidcompound or prodrug.

A more particular compound of formula I is one wherein

A³, A⁴, A⁵ and A⁶, together with the two carbons to which they areattached, complete a substituted benzene in which A³ is CR³, A⁴ is CR⁴,A⁵ is CR⁵, and A⁶ is CR⁶; wherein

R³ is hydrogen;

one of R⁴ and R⁵ is hydrogen, methyl, fluoro, chloro, trifluoromethyl,trifluoromethoxy, R^(f)O₂— or R^(g)NH—;

the other of R⁴ and R⁵ is hydrogen; and

R⁶ is hydrogen;

in which R^(f) is hydrogen, (1-4C)alkyl or benzyl; R^(g) is hydrogen orR^(h)SO₂—; and R^(h) is (1-4C)alkyl or dimethylamino;

L¹ is —CO—NH— such that —L¹—Q¹ is —CO—NH—Q¹;

Q¹ is 2-pyridinyl (which bears a methyl, fluoro or chloro substituent atthe 5-position), 3-pyridinyl (which bears a methyl, fluoro or chlorosubstituent at the 6-position), 2-pyrimidinyl (which may bear a methyl,fluoro or chloro substituent at the 5-position) or 3-pyridazinyl (whichmay bear a methyl, fluoro or chloro substituent at the 6-position);

R² is —L²—Q² in which —L²— is —NH—CO—, —NH—CO—X—, —NH—CO—O—X—,—NH—CO—NH—X—, —NH—CH₂— or —O—CH₂—; and Q² is Q^(2A), Q^(2B), Q^(2C),Q^(2D), Q^(2E) or Q^(2F) wherein X is a single bond or methylene and thevalues of L² and Q² are together selected from —NH—CO—X—Q^(2A),—NH—CO—O—X—Q^(2A), —NH—CO—NH—X—Q^(2A), —NH—CH₂—Q^(2A), —O—CH₂—Q^(2A),—NH—CO—X—Q^(2B), —NH—CO—Q^(2C), —NH—CO—Q^(2D), —NH—CO—Q^(2E) and—NH—CO—Q^(2F) in which:

Q^(2A) (showing the L² to which it is attached) is

 in which

each of m and n independently is 0 or 1, and

R^(2A) is hydrogen, —CHR^(y)R^(z), —CHR^(w)R^(x), or 4-pyridinyl (whichis unsubstituted or bears a substituent R^(y) at the 2- or 3-position)wherein

R^(v) is methyl, hydroxymethyl, {(1-2C)alkoxy}carbonyl; cyano,carbamoyl, thiocarbamoyl, or N-hydroxyamidino;

each of R^(w) and R^(x) independently is hydrogen or (1-3C)normal alkyl;or —CHR^(w)R^(x) is 2-indanyl or (showing the nitrogen to which it isattached) is

 in which T is a single bond or methylene and U is methylene, oxy,thioxy or imino (which may bear a methyl substituent), or T isethan-1,1-diyl and U is a single bond or methylene;

R^(y) is hydrogen or methyl; and

R^(z) is isopropyl, t-butyl, (3-6C)cycloalkyl, phenyl (which isunsubstituted or bears one or more substituents independently selectedfrom halo, methyl, methoxy and hydroxy), 4-quinolinyl or heteroaryl(which heteroaryl is a 5-membered aromatic ring which includes one tofour heteroatoms selected from sulfur, oxygen and nitrogen or is a6-membered aromatic ring which includes one to three nitrogen atoms,wherein the heteroaryl is attached at carbon and may bear one or moremethyl substituents on carbon or nitrogen);

Q^(2B) is 1-piperazinyl which bears at the 4-position the group R^(2A)(defined as above);

Q^(2C) is 3,4-didehydropiperidin-4-yl which bears at the 1-position thegroup R^(2A) (defined as above);

Q^(2D) is cyclohexyl which bears at the 4-position the group—NR^(s)R^(t) in which each of R^(s) and R^(t) independently is hydrogenor methyl or R^(s) and R^(t) together are trimethylene ortetramethylene;

Q^(2E) is 1-piperidinyl which bears at the 4-position the group—NR^(s)R^(t) (defined as above); and

Q^(2F) (showing the L² to which it is attached) is

 in which R^(o) is hydrogen and R^(p) is acetylamino, 1-hydroxyethyl,1-hydroxy-1-methylethyl, 1-methoxy-1-methylethyl, 4-piperidinyl,4-pyridinyl, dimethylaminosulfonyl or —J—R^(q) in which J is a singlebond, methylene, carbonyl, oxy, —S(O)_(q)— (wherein q is 0, 1 or 2), or—NR^(r)— (wherein R^(r) is hydrogen or methyl); and R^(q) is(1-6C)alkyl, phenyl, 3-pyridyl or 4-pyridyl.

A pharmaceutically acceptable salt of an antithrombotic agent of theinstant invention includes one which is an acid-addition salt made froma basic compound of formula I and an acid which provides apharmaceutically acceptable anion, as well as a salt which is made froman acidic compound of formula I and a base which provides apharmaceutically acceptable cation. Thus, a salt of a novel compound offormula I as provided herein made with an acid or base which affords apharmaceutically acceptable counterion provides a particular aspect ofthe invention. Examples of such acids and bases are providedhereinbelow.

As an additional aspect of the invention there is provided apharmaceutical formulation comprising in association with apharmaceutically acceptable carrier, diluent or excipient, a novelcompound of formula I (or a pharmaceutically acceptable salt thereof) asprovided in any of the descriptions herein.

In addition, there is provided the use of a factor Xa inhibitingcompound of formula I (or prodrug or salt) as described herein as anactive ingredient in the manufacture of a medicament for use inproducing an anticoagulant or antithrombotic effect.

The present invention also provides a method of inhibiting coagulationin a mammal comprising administering to a mammal in need of treatment, acoagulation inhibiting dose of a factor Xa inhibiting compound offormula I having any of the definitions herein.

The present invention further provides a method of inhibiting factor Xacomprising administering to a mammal in need of treatment, a factor Xainhibiting dose of a factor Xa inhibiting compound of formula I havingany of the definitions herein.

Further, the present invention provides a method of treating athromboembolic disorder comprising administering to a mammal in need oftreatment, an effective dose of a factor Xa inhibiting compound offormula I having any of the definitions herein.

In addition, there is provided the use of a factor Xa inhibitingcompound of formula I having any of the definitions herein for themanufacture of a medicament for treatment of a thromboembolic disorder.

As an additional feature of the invention there is provided apharmaceutical formulation comprising in association with apharmaceutically acceptable carrier, diluent or excipient, a prodrug ofa factor Xa inhibiting compound of formula I (or of a pharmaceuticallyacceptable salt thereof) as provided in any of the descriptions herein.

In this specification, the following definitions are used, unlessotherwise described: Halo is fluoro, chloro, bromo or iodo. Alkyl,alkoxy, etc. denote both straight and branched groups; but reference toan individual radical such as “propyl” embraces only the straight chain(“normal”) radical, a branched chain isomer such as “isopropyl” beingspecifically denoted.

Particular values are listed below for radicals, substituents, andranges, for illustration only, and they do not exclude other definedvalues or other values within defined ranges for the radicals andsubstituents.

For an alkyl group or the alkyl portion of an alkyl containing groupsuch as, for example alkoxy, a particular value for (1-2C)alkyl ismethyl or ethyl, and more particularly is methyl; for (1-3C)normal alkylis methyl, ethyl or propyl; for (1-4C)alkyl is methyl, ethyl, propyl,isopropyl, butyl, isobutyl, or t-butyl, and more particularly is methyl,isopropyl, butyl or t-butyl; for (1-6C)alkyl is methyl, ethyl, propyl,butyl, pentyl or hexyl, and more particularly is methyl, butyl, orhexyl. A particular value for (3-6C)cycloalkyl is cyclopropyl,cyclobutyl, cyclopenytyl or cyclohexyl. A particular value for halo isbromo or chloro, and more particularly is chloro.

A particular value for Q¹ is 5-chloropyridin-2-yl, 5-fluoropyridin-2-yl,or 6-chloropyridazin-3-yl. A particular value for R² is(1-isopropylpiperidin-4-ylcarbonyl)amino,(1-cyclohexylpiperidin-4-ylcarbonyl)amino,(4-isopropylpiperazin-1-ylcarbonyl)amino,[1-(tetrahydropyran-4-yl)piperidin-4-ylcarbonyl]amino,[4-(1-pyrrolidinyl)piperidin-1-ylcarbonyl]amino,[1-(4-pyridinyl)piperidin-4-ylmethyl]amino,[1-(2-carboxypyridin-4-yl)piperidin-4-ylmethyl]amino, or[1-(2-methoxycarbonylpyridin-4-yl)piperidin-4-ylmethyl]amino.

A particular set of values for R³-R⁶ is that each of R³-R⁶ is hydrogen.Another particular set of values for R³-R⁶ is that each of R³, R⁴ and R⁶is hydrogen and R⁵ is chloro or fluoro. A further particular set ofvalues for R³-R⁶ is that each of R³, R⁴ and R⁶ is hydrogen and R⁵ isR^(a) wherein R^(a) is phenyl, furanyl, thienyl, 2-isothiazolyl orpyridyl.

A particular species is one those listed below as example 44, 51, 69,70, 75, 80, 84, 96 or 97.

It will be appreciated that certain compounds of formula I (or salts orprodrugs, etc.) may exist in, and be isolated in, isomeric forms,including tautomeric forms, cis- or trans-isomers, as well as opticallyactive, racemic, or diastereomeric forms. It is to be understood thatthe present invention encompasses a compound of formula I in any of thetautomeric forms or as an a mixture thereof; or as a mixture ofdiastereomers, as well as in the form of an individual diastereomer, andthat the present invention encompasses a compound of formula I as amixture of enantiomers, as well as in the form of an individualenantiomer, any of which mixtures or form possesses inhibitoryproperties against factor Xa, it being well known in the art how toprepare or isolate particular forms and how to determine inhibitoryproperties against factor Xa by standard tests including those describedbelow.

In addition, a compound of formula I (or salt or prodrug, etc.) mayexhibit polymorphism or may form a solvate with water or an organicsolvent. The present invention also encompasses any such polymorphicform, any solvate or any mixture thereof.

A prodrug of a compound of formula I may be one formed in a conventionalmanner with a functional group of the compound, such as with an amino,hydroxy or carboxy group.

A compound of formula I may be prepared by processes which includeprocesses known in the chemical art for the production of structurallyanalogous compounds or by a novel process described herein. A processfor the preparation of a compound of formula I (or a pharmaceuticallyacceptable salt thereof) and novel intermediates for the manufacture ofa compound of formula I as defined above provide further features of theinvention and are illustrated by the following procedures in which themeanings of the generic radicals are as defined above, unless otherwisespecified. It will be recognized that it may be preferred or necessaryto prepare a compound of formula I in which a functional group isprotected using a conventional protecting group, then to remove theprotecting group to provide the compound of formula I.

Thus, there is provided a process for preparing a compound of formula I(or a pharmaceutically acceptable salt thereof) as provided in any ofthe above descriptions which is selected from any of those described inthe examples, including the following.

(A) For a compound of formula I in which —L²—Q², is —NH—CO—O²,—NH—CO—X—Q², —NH—CO—O—X—Q² or —NH—CO—NH—X—Q², acylating an amine offormula II,

using a corresponding acid of formula HO—CO—O², HO—CO—X—Q²,HO—CO—O—X—Q², or HO—CO—NH—X—Q², or an activated derivative thereof.Typical activated derivatives include the acid halides, activatedesters, including 4-nitrophenyl esters and those derived from couplingreagents, as well as (when the product is a urea) isocyanates. Typicalprocedures include those described at example 1-D, example 4-B andexample 9-A.

(B) For a compound of formula I in which —L²—Q² is —O—CH₂—Q^(2A),akylating a phenol of formula III

using a reagent of formula Y—CH²—Q^(2A) in which Y is a conventionalleaving group. As used herein, a leaving group “Y” is a moiety which isdisplaced in a nucleophilic substitution reaction, for example a halogroup (such as chloro, bromo or iodo), a sulfonate ester group (such asmethylsulfonyloxy, p-toluylsulfonyloxy or trifluoromethylsulfonyloxy),or the reactive species derived from treating an alcohol withtriphenylphospine, diethyl azodicarboxylate and triethyl amine (in aMitsunobu reaction), for example as described at example 8-B.

(C) Acylating an amine of formula H₂N—Q¹, or a deprotonated derivativethereof, using an acid of formula IV, or an activated derivativethereof.

Typical deprotonated derivatives of the amine H₂N—Q¹ include, forexample, that derived from treatment of the amine with anorganomagnesium reagent, for example, with allylmagnesium bromide ormethylmagnesium bromide. Typical activated derivatives include the acidhalides, activated esters, including 4-nitrophenyl esters and thosederived from coupling reagents.

For a compound of formula I in which R² is of the form —NH—CO—Q², theactivated acid may be a [1,3] oxazine of formula IVa,

wherein Q² represents, for example, Q^(2A), Q^(2B), Q^(2C), Q^(2D),Q^(2E) or Q^(2F). A typical procedure is one such as described atexample 46-D (using potassium cyanide to promote the reaction) or atexample 51-D.

For a compound of formula I in which R² is of the form —NH—CH₂—Q², theactivated acid may be an anhydride of formula IVb,

wherein Q² represents Q^(2A). A typical procedure is similar to thatdescribed at example 51-D for use with the activated acid of formulaIVa.

(D) For a compound of formula I in which R² is —NH—CH₂—Q^(2A),alkylating an amine of formula II directly, using a compound of formulaY—CH₂—Q^(2A), or (preferably) indirectly by reductive alkylation usingan aldehyde of formula Q^(2A)—CHO. In the reductive alkylation theintermediate imine of formula V or acid addition salt thereof (whichprovide a further aspect of the invention),

may be formed in situ and reduced directly, or may be isolated prior toreduction, for example as described at examples 47-D and 59-B where thereduction is carried out using borane trimethylamine complex in glacialacetic acid.

(E) For a compound of formula I in which R² is —NH—CO—O—X—Q^(2A), or—NH—CO—NH—X—Q^(2A), acylating an alcohol of formula HO—X—Q^(2A) or anamine of formula NH₂—X—Q^(2A), using an activated derivative of an acidof formula VI,

particularly, the corresponding isocyanate or 4-nitrophenyl ester. Theprocedure may be carried out analogously to the starting materialpreparation of example 51-A.

(F) For a compound of formula I in which R² is —NH—CO—X—Q^(2B) in whichX is a single bond, acylating at the 1-position a piperazine of formulaH—Q^(2B), using an activated derivative of an acid of formula VI,particularly, the corresponding isocyanate or 4-nitrophenyl ester. Theprocedure may be carried out analogously to the starting materialpreparation of example 51-A or of example 95-A.

(G) For a compound of formula I in which R² is —NH—CO—X—Q^(2B) in whichX is methylene, alkylating at the 1-position a piperazine of formulaH—Q^(2B), using an alkylating agent of formula VII

in which Y is a leaving group, for example as described at example 45-B.

(H) For a compound of formula I in which R^(2A) is methylsulfonyl,substituting the amino nitrogen of a corresponding compound of formula Iin which R^(2A) is hydrogen using an activated derivative ofmethanesulfonic acid, for example using methanesulfonyl chloride in thepresence of added base.

(I) For a compound of formula I in which R^(2A) is —CHR^(y)R^(z) or—CHR^(w)R^(x), alkylating the amino nitrogen of a corresponding compoundof formula I in which R^(2A) is hydrogen using an alkylating agent offormula Y—CHR^(y)R^(z) or Y—CHR^(w)R^(x) or, preferably, reductivelyalkylating the amine using a compound of formula R^(y)—CO—R^(z) orR^(w)—CO—R^(x). The direct alkylation may be completed in a polarsolvent in the presence of a base, for example as described at example102. The reductive alkylation conveniently is carried out, for example,using sodium cyanoborohydride in methanol/acetic acid as described atexample 9-C and at examples 48 and 112 or using sodiumtriacetoxyborohydride in an inert solvent such as 1,2-dichloroethanealong with an excess of the carbonyl compound and glacial acetic acid asdescribed at example 27.

(J) For a compound of formula I in which R^(2A) is 4-pyridinyl (which isunsubstituted or bears a substituent R^(v) at the 2- or 3-position),substituting the amino nitrogen of a corresponding compound of formula Iin which R^(2A) is hydrogen using a corresponding pyridine reagentbearing a leaving group Y at the 4-position, for example with a4-chloropyridine in ethanol as described at example 52 or at example 85.

(K) For a compound of formula I in which R^(2A) is 4-pyridinyl in whichR^(v) is alkoxycarbonyl, esterifying a corresponding compound of formulaI in which R^(v) is carboxy, for example as described at example 97.

(L) For a compound of formula I in which R^(2A) is 4-pyridinyl in whichR^(v) is hydroxymethyl, reducing the ester of a corresponding compoundof formula I in which R^(v) is alkoxycarbonyl.

(M) For a compound of formula I in which R^(2A) is 4-pyridinyl in whichR^(v) is carbamoyl, amidating the ester of a corresponding compound offormula I in which R^(v) is alkoxycarbonyl.

(N) For a compound of formula I in which R^(2A) is 4-pyridinyl in whichR^(v) is thiocarbamoyl, adding H₂S to the nitrile of a correspondingcompound of formula I in which R^(v) is cyano.

(O) For a compound of formula I in which R^(2A) is 4-pyridinyl in whichR^(v) is N-hydroxyamidino, adding H₂NOH to the nitrile of acorresponding compound of formula I in which R^(v) is cyano. Theaddition may be direct or indirect, such as via an imidate ester or bytreating a compound in which R^(v) is thiocarbamoyl with methyl iodideto form a thioimidate ester, then treatment with hydroxylamine

(P) For a compound of formula I in which R^(2A) is 4-pyridinyl in whichR^(v) is carboxy, decomposing the ester of a corresponding compound offormula I in which R^(v) is alkoxycarbonyl.

(Q) For a compound of formula I in which —NR^(s)R^(t) is other thanamino, alkylating a corresponding compound of formula I in which—NR^(s)R^(t) is amino using a conventional method. When R^(s) and R^(t)together are trimethylene or tetramethylene, a difunctional alkylatingagent, such as 1,3-dibromopropane or 1,4-dibromobutane is preferred.

(R) For a compound of formula I which bears —NR^(s)R^(t), reductivelyalkylating H—NR^(s)R^(t) using a corresponding compound but in which thecarbon to bear the —NR^(s)R^(t) group bears an oxo group, for example,using a procedure similar to one of procedure (I) above, as described atexample 98.

(S) For a compound of formula I in which R^(p) is1-hydroxy-1-methylethyl, adding a methyl group to the carbonyl group ofa corresponding compound of formula I in which R^(p) is acetyl using anorganometallic reagent such as, for example, methylmagnesium bromide.

(T) For a compound of formula I in which R^(p) is1-methoxy-1-methylethyl, treating a corresponding compound of formula Iin which R^(p) is 1-hydroxy-1-methylethyl with methanol and an acidcatalyst.

(U) For a compound of formula I in which R⁴ or R⁵ is amino, reducing thenitro group of a compound corresponding to a compound of formula I butin which R⁴ or R⁵ is nitro.

(V) For a compound of formula I in which R⁴ or R⁵ is R^(g)NH— and R^(g)is R^(h)SO₂—, substituting the amino group of a corresponding compoundof formula I in which R⁴ or R⁵ is amino using an activated derivative ofthe sulfonic acid R^(h)SO₂—OH.

Whereafter, for any of the above procedures, when a functional group isprotected using a protecting group, removing the protecting group.

Whereafter, for any of the above procedures, when a pharmaceuticallyacceptable salt of a compound of formula I is required, it is obtainedby reacting the basic form of a basic compound of formula I with an acidaffording a physiologically acceptable counterion or the acidic form ofan acidic compound of formula I with a base affording a physiologicallyacceptable counterion or by any other conventional procedure.

A novel intermediate or starting material compound such as, for example,a novel compound of formula II, III, IV or VI, etc., provides a furtheraspect of the invention. The various starting materials may be made byprocesses which include processes known in the chemical art for theproduction of structurally analogous compounds or by a novel processdescribed herein or one analogous thereto.

As mentioned above, a compound corresponding to a compound of formula Ibut in which a functional group is protected may serve as anintermediate for a compound of formula I. Accordingly, such a protectedintermediate for a novel compound of formula I provides a further aspectof the invention. Thus, as one particular aspect of the invention, thereis provided a compound corresponding to a novel compound of formula I asdefined above in which R⁴ is hydroxy, but in which the correspondingsubstituent is —OP^(p) in place of hydroxy, wherein P^(p) is a phenolprotecting group other than (1-4C)alkyl or benzyl. Phenol protectinggroups are well known in the art, for example as described in T. W.Greene and P. G. M. Wuts, “Protecting Groups in Organic Synthesis”(1991). Further, P^(p) may denote a functionalized resin, for example asdisclosed in H. V. Meyers, et al., Molecular Diversity, (1995), 1,13-20.

As mentioned above, the invention includes a pharmaceutically acceptablesalt of the factor Xa inhibiting compound defined by the above formulaI. A basic compound of this invention possesses one or more functionalgroups sufficiently basic to react with any of a number of inorganic andorganic acids affording a physiologically acceptable counterion to forma pharmaceutically acceptable salt. Acids commonly employed to formpharmaceutically acceptable acid addition salts are inorganic acids suchas hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid,phosphoric acid, and the like, and organic acids such asp-toluenesulfonic acid, methanesulfonic acid, oxalic acid,p-bromobenzenesulfonic acid, carbonic acid, succinic acid, citric acid,benzoic acid, acetic acid, and the like. Examples of suchpharmaceutically acceptable salts thus are the sulfate, pyrosulfate,bisulfate, sulfite, bisulfite, phosphate, monohydrogenphosphate,dihydrogenphosphate, metaphosphate, pyrophosphate, chloride, bromide,iodide, acetate, propionate, decanoate, caprylate, acrylate, formate,isobutyrate, caproate, heptanoate, propiolate, oxalate, malonate,succinate, suberate, sebacate, fumarate, maleate, butyne-1,4-dioate,hexyne-1,6-dioate, benzoate, chlorobenzoate, methylbenzoate,dinitrobenzoate, hydroxybenzoate, methoxybenzoate, phthalate, sulfonate,xylenesulfonate, phenylacetate, phenylpropionate, phenylbutyrate,citrate, lactate, gamma-hydroxybutyrate, glycollate, tartrate,methanesulfonate, propanesulfonate, naphthalene-1-sulfonate,naphthalene-2-sulfonate, mandelate, and the like. Preferredpharmaceutically acceptable acid addition salts include those formedwith mineral acids such as hydrochloric acid, hydrobromic acid andsulfuric acid.

For a compound of formula I which bears an acidic moiety, such as acarboxy group, a pharmaceutically acceptable salt may be made with abase which affords a pharmaceutically acceptable cation, which includesalkali metal salts (especially sodium and potassium), alkaline earthmetal salts (especially calcium and magnesium), aluminum salts andammonium salts, as well as salts made from physiologically acceptableorganic bases such as triethylamine, morpholine, piperidine andtriethanolamine

If not commercially available, a necessary starting material for thepreparation of a compound of formula I may be prepared by a procedurewhich is selected from standard techniques of organic chemistry,including aromatic and heteroaromatic substitution and transformation,from techniques which are analogous to the syntheses of known,structurally similar compounds, and techniques which are analogous tothe above described procedures or procedures described in the Examples.It will be clear to one skilled in the art that a variety of sequencesis available for the preparation of the starting materials. Startingmaterials which are novel provide another aspect of the invention.

Selective methods of substitution, protection and deprotection are wellknown in the art for preparation of a compound such as one of formulaII, III, IV or VI discussed above.

Generally, a basic compound of the invention is isolated best in theform of an acid addition salt. A salt of a compound of formula I formedwith an acid such as one of those mentioned above is useful as apharmaceutically acceptable salt for administration of theantithrombotic agent and for preparation of a formulation of the agent.Other acid addition salts may be prepared and used in the isolation andpurification of the compounds.

As noted above, the optically active isomers and diastereomers of thecompounds of formula I are also considered part of this invention. Suchoptically active isomers may be prepared from their respective opticallyactive precursors by the procedures described above, or by resolving theracemic mixtures. This resolution can be carried out by derivatizationwith a chiral reagent followed by chromatography or by repeatedcrystallization. Removal of the chiral auxiliary by standard methodsaffords substantially optically pure isomers of the compounds of thepresent invention or their precursors. Further details regardingresolutions can be obtained in Jacques, et al., Enantiomers, Racemates,and Resolutions, John Wiley & Sons, 1981.

The compounds of the invention are believed to selectively inhibitfactor Xa over other proteinases and nonenzyme proteins involved inblood coagulation without appreciable interference with the body'snatural clot lysing ability (the compounds have a low inhibitory effecton fibrinolysis). Further, such selectivity is believed to permit usewith thrombolytic agents without substantial interference withthrombolysis and fibrinolysis.

The invention in one of its aspects provides a method of inhibitingfactor Xa in mammals comprising administering to a mammal in need oftreatment an effective (factor Xa inhibiting) dose of a compound offormula I.

In another of its aspects, the invention provides a method of treating athromboembolic disorder comprising administering to a mammal in need oftreatment an effective (thromboembolic disorder therapeutic and/orprophylactic amount) dose of a compound of formula I.

The invention in another of its aspects provides a method of inhibitingcoagulation in a mammal comprising administering to a mammal in need oftreatment an effective (coagulation inhibiting) dose of a compound offormula I.

The factor Xa inhibition, coagulation inhibition and thromboembolicdisorder treatment contemplated by the present method includes bothmedical therapeutic and/or prophylactic treatment as appropriate.

In a further embodiment, the invention relates to treatment, in a humanor animal, of a condition where inhibition of factor Xa is required. Thecompounds of the invention are expected to be useful in mammals,including man, in treatment or prophylaxis of thrombosis andhypercoagulability in blood and tissues. Disorders in which thecompounds have a potential utility are in treatment or prophylaxis ofthrombosis and hypercoagulability in blood and tissues. Disorders inwhich the compounds have a potential utility, in treatment and/orprophylaxis, include venous thrombosis and pulmonary embolism, arterialthrombosis, such as in myocardial ischemia, myocardial infarction,unstable angina, thrombosis-based stroke and peripheral arterialthrombosis. Further, the compounds have expected utility in thetreatment or prophylaxis of atherosclerotic disorders (diseases) such ascoronary arterial disease, cerebral arterial disease and peripheralarterial disease. Further, the compounds are expected to be usefultogether with thrombolytics in myocardial infarction. Further, thecompounds have expected utility in prophylaxis for reocclusion afterthrombolysis, percutaneous transluminal angioplasty (PTCA) and coronarybypass operations. Further, the compounds have expected utility inprevention of rethrombosis after microsurgery. Further, the compoundsare expected to be useful in anticoagulant treatment in connection withartificial organs, including joint replacement, and cardiac valves.Further, the compounds have expected utility in anticoagulant treatmentin hemodialysis and disseminated intravascular coagulation. A furtherexpected utility is in rinsing of catheters and mechanical devices usedin patients in vivo, and as an anticoagulant for preservation of blood,plasma and other blood products in vitro. Still further, the compoundshave expected utility in other diseases where blood coagulation could bea fundamental contributing process or a source of secondary pathology,such as cancer, including metastasis, inflammatory diseases, includingarthritis, and diabetes. The anti-coagulant compound is administeredorally or parenterally, e.g. by intravenous infusion (iv), intramuscularinjection (im) or subcutaneously (sc).

The specific dose of a compound administered according to this inventionto obtain therapeutic and/or prophylactic effects will, of course, bedetermined by the particular circumstances surrounding the case,including, for example, the compound administered, the rate ofadministration, the route of administration, and the condition beingtreated.

A typical daily dose for each of the above utilities is between about0.01 mg/kg and about 1000 mg/kg. The dose regimen may vary e.g. forprophylactic use a single daily dose may be administered or multipledoses such as 3 or 5 times daily may be appropriate. In critical caresituations a compound of the invention is administered by iv infusion ata rate between about 0.01 mg/kg/h and about 20 mg/kg/h and preferablybetween about 0.1 mg/kg/h and about 5 mg/kg/h.

The method of this invention also is practiced in conjunction with aclot lysing agent e.g. tissue plasminogen activator (t-PA), modifiedt-PA, streptokinase or urokinase. In cases when clot formation hasoccurred and an artery or vein is blocked, either partially or totally,a clot lysing agent is usually employed. A compound of the invention canbe administered prior to or along with the lysing agent or subsequent toits use, and preferably further is administered along with aspirin toprevent the reoccurrence of clot formation.

The method of this invention is also practiced in conjunction with aplatelet glycoprotein receptor (IIb/IIIa) antagonist, that inhibitsplatelet aggregation. A compound of the invention can be administeredprior to or along with the IIb/IIIa antagonist or subsequent to its useto prevent the occurrence or reoccurrence of clot formation.

The method of this invention is also practiced in conjunction withaspirin. A compound of the invention can be administered prior to oralong with aspirin or subsequent to its use to prevent the occurrence orreoccurrence of clot formation. As stated above, preferably a compoundof the present invention is administered in conjunction with a clotlysing agent and aspirin.

This invention also provides a pharmaceutical composition for use in theabove described therapeutic method. A pharmaceutical composition of theinvention comprises an effective factor Xa inhibiting amount of acompound of formula I in association with a pharmaceutically acceptablecarrier, excipient or diluent.

The active ingredient in such formulations comprises from 0.1 percent to99.9 percent by weight of the formulation. By “pharmaceuticallyacceptable” it is meant the carrier, diluent or excipient must becompatible with the other ingredients of the formulation and notdeleterious to the recipient thereof.

For oral administration the antithrombotic compound is formulated ingelatin capsules or tablets which may contain excipients such asbinders, lubricants, disintegration agents and the like. For parenteraladministration the antithrombotic is formulated in a pharmaceuticallyacceptable diluent e.g. physiological saline (0.9 percent), 5 percentdextrose, Ringer's solution and the like.

The compound of the present invention can be formulated in unit dosageformulations comprising a dose between about 0.1 mg and about 1000 mg.Preferably the compound is in the form of a pharmaceutically acceptablesalt such as for example the sulfate salt, acetate salt or a phosphatesalt. An example of a unit dosage formulation comprises 5 mg of acompound of the present invention as a pharmaceutically acceptable saltin a 10 mL sterile glass ampoule. Another example of a unit dosageformulation comprises about 10 mg of a compound of the present inventionas a pharmaceutically acceptable salt in 20 mL of isotonic salinecontained in a sterile ampoule.

The compounds can be administered by a variety of routes including oral,rectal, transdermal, subcutaneous, intravenous, intramuscular, andintranasal. The compounds of the present invention are preferablyformulated prior to administration.

The present pharmaceutical compositions are prepared by known proceduresusing well known and readily available ingredients. The compositions ofthis invention may be formulated so as to provide quick, sustained, ordelayed release of the active ingredient after administration to thepatient by employing procedures well known in the art. In making thecompositions of the present invention, the active ingredient willusually be admixed with a carrier, or diluted by a carrier, or enclosedwithin a carrier which may be in the form of a capsule, sachet, paper orother container. When the carrier serves as a diluent, it may be asolid, semi-solid or liquid material which acts as a vehicle, excipientor medium for the active ingredient. Thus, the compositions can be inthe form of tablets, pills, powders, lozenges, sachets, cachets,elixirs, suspensions, emulsions, solutions, syrups, aerosols, (as asolid or in a liquid medium), soft and hard gelatin capsules,suppositories, sterile injectable solutions, sterile packaged powders,and the like.

The following formulation examples are illustrative only and are notintended to limit the scope of the invention in any way. “Activeingredient,” of course, means a compound according to formula I or apharmaceutically acceptable salt or solvate thereof.

Formulation 1

Hard gelatin capsules are prepared using the following ingredients:

Quantity (mg/capsule) Active ingredient 250 Starch, dried 200 Magnesiumstearate 10 Total 460 mg

Formulation 2

A tablet is prepared using the ingredients below:

Quantity (mg/tablet) Active ingredient 250 Cellulose, microcrystalline400 Silicon dioxide, fumed 10 Stearic acid 5 Total 665 mg

The components are blended and compressed to form tablets each weighing665 mg.

Formulation 3

An aerosol solution is prepared containing the following components:

Weight Active ingredient 0.25 Ethanol 29.75 Propellant 22(Chlorodifluoromethane) 70.00 Total 100.00

The active compound is mixed with ethanol and the mixture added to aportion of the propellant 22, cooled to −30° C. and transferred to afilling device. The required amount is then fed to a stainless steelcontainer and diluted with the remainder of the propellant. The valveunits are then fitted to the container.

Formulation 4

Tablets, each containing 60 mg of active ingredient, are made asfollows:

Active ingredient 60 mg Starch 45 mg Microcrystalline cellulose 35 mgPolyvinylpyrrolidone (as 10% solution in 4 mg water) Sodiumcarboxymethyl starch 4.5 mg Magnesium stearate 0.5 mg Talc 1 mg Total150 mg

The active ingredient, starch and cellulose are passed through a No. 45mesh U.S. sieve and mixed thoroughly. The aqueous solution containingpolyvinylpyrrolidone is mixed with the resultant powder, and the mixturethen is passed through a No. 14 mesh U.S. sieve. The granules soproduced are dried at 50° C. and passed through a No. 18 mesh U.S.Sieve. The sodium carboxymethyl starch, magnesium stearate and talc,previously passed through a No. 60 mesh U.S. sieve, are then added tothe granules which, after mixing, are compressed on a tablet machine toyield tablets each weighing 150 mg.

Formulation 5

Capsules, each containing 80 mg of active ingredient, are made asfollows:

Active ingredient 80 mg Starch 59 mg Microcrystalline cellulose 59 mgMagnesium stearate 2 mg Total 200 mg

The active ingredient, cellulose, starch, and magnesium stearate areblended, passed through a No. 45 mesh U.S. sieve, and filled into hardgelatin capsules in 200 mg quantities.

Formulation 6

Suppositories, each containing 225 mg of active ingredient, are made asfollows:

Active ingredient 225 mg Saturated fatty acid glycerides 2,000 mg Total2,225 mg

The active ingredient is passed through a No. 60 mesh U.S. sieve andsuspended in the saturated fatty acid glycerides previously melted usingthe minimum heat necessary. The mixture is then poured into asuppository mold of nominal 2 g capacity and allowed to cool.

Formulation 7

Suspensions, each containing 50 mg of active ingredient per 5 mL dose,are made as follows:

Active ingredient 50 mg Sodium carboxymethyl cellulose 50 mg Syrup 1.25mL Benzoic acid solution 0.10 mL Flavor q.v. Color q.v. Purified waterto total 5 mL

The active ingredient is passed through a No. 45 mesh U.S. sieve andmixed with the sodium carboxymethyl cellulose and syrup to form a smoothpaste. The benzoic acid solution, flavor and color are diluted with aportion of the water and added, with stirring. Sufficient water is thenadded to produce the required volume.

Formulation 8

An intravenous formulation may be prepared as follows:

Active ingredient 100 mg Isotonic saline 1,000 mL

The solution of the above ingredients generally is administeredintravenously to a subject at a rate of 1 mL per minute.

The ability of a compound of the present invention to be an effectiveand orally active factor Xa inhibitor may be evaluated in one or more ofthe following assays or in other standard assays known to those in theart.

The inhibition by a compound of the inhibition of a serine protease ofthe human blood coagulation system or of the fibrinolytic system, aswell as of trypsin, is determined in vitro for the particular enzyme bymeasuring its inhibitor binding affinity in an assay in which the enzymehydrolyzes a particular chromogenic substrate, for example as describedin Smith, G. F.; Gifford-Moore, D.; Craft, T. J.; Chirgadze, N.;Ruterbories, K. J.; Lindstrom, T. D.; Satterwhite, J. H. Efegatran: ANew Cardiovascular Anticoagulant. New Anticoagulants for theCardiovascular Patient; Pifarre, R., Ed.; Hanley & Belfus, Inc.:Philadelphia, 1997; pp. 265-300. The inhibitor binding affinity ismeasured as apparent association constant Kass which is the hypotheticalequilibrium constant for the reaction between enzyme and the testinhibitor compound (I). Enzyme + I ⇄ Enzyme − I${Kass} = \frac{\left\lbrack {{Enzyme} - I} \right\rbrack}{\left\lbrack {({Enzyme}) \times (I)} \right\rbrack}$

Conveniently, enzyme inhibition kinetics are performed in 96-wellpolystyrene plates and reaction rates are determined from the rate ofhydrolysis of appropriate p-nitroanilide substrates at 405 nm using aThermomax plate reader from Molecular Devices (San Francisco, Calif.).The same protocol is followed for all enzymes studied: 50 μL buffer(0.03 M Tris, 0.15 M NaCl pH 7) in each well, followed by 25 μL ofinhibitor solution (in 100% methanol, or in 50% v:v aqueous methanol)and 25 μL enzyme solution; within two minutes, 150 μL aqueous solutionof chromogenic substrate (0.25 mg/mL) is added to start the enzymaticreaction. The rates of chromogenic substrate hydrolysis reactionsprovide a linear relationship with the enzymes studied such that freeenzyme can be quantitated in reaction mixtures. Data is analyzeddirectly as rates by the Softmax program to produce [free enzyme]calculations for tight-binding Kass determinations. For apparent Kassdeterminations, 1.34 nM human factor Xa is used to hydrolyze 0.18 mMBzIle-Glu-Gly-Arg-pNA; 5.9 nM human thrombin or 1.4 nM bovine trypsin isused to hydrolyze 0.2 mM BzPhe-Val-Arg-pNA; 3.4 nM human plasmin is usedwith 0.5 mM HD-Val-Leu-Lys-pNA; 1.2 nM human nt-PA is used with 0.81 mMHD-Ile-Pro-Arg-pNA; and 0.37 nM urokinase is used with 0.30 mMpyro-gfsGlu-Gly-Arg-pNA.

Kass is calculated for a range of concentrations of test compounds andthe mean value reported in units of liter per mole. In general, a factorXa inhibiting compound of formula I of the instant invention, asexemplified herein, exhibits a Kass of 0.1 to 0.5×10⁶ L/mole or muchgreater.

The factor Xa inhibitor preferably should spare fibrinolysis induced byurokinase, tissue plasminogen activator (t-PA) and streptokinase. Thiswould be important to the therapeutic use of such an agent as an adjunctto streptokinase, tp-PA or urokinase thrombolytic therapy and to the useof such an agent as an endogenous fibrinolysis-sparing (with respect tot-PA and urokinase) antithrombotic agent. In addition to the lack ofinterference with the amidase activity of the fibrinolytic proteases,such fibrinolytic system sparing can be studied by the use of humanplasma clots and their lysis by the respective fibrinolytic plasminogenactivators.

Materials

Dog plasma is obtained from conscious mixed-breed hounds (either sexButler Farms, Clyde, New York, U.S.A.) by venipuncture into 3.8 percentcitrate. Fibrinogen is prepared from fresh dog plasma and humanfibrinogen is prepared from in-date ACD human blood at the fraction I-2according to previous procedures and specification. Smith, Biochem. J.,85, 1-11 (1980; and Smith, et al., Biochemistry, 11, 2958-2967, (1972).Human fibrinogen (98 percent pure/plasmin free) is from AmericanDiagnostica, Greenwich, Conn. Radiolabeling of fibrinogen I-2preparations is performed as previously reported. Smith, et al.,Biochemistry, 11, 2958-2967, (1972). Urokinase is purchased from LeoPharmaceuticals, Denmark, as 2200 Ploug units/vial. Streptokinase ispurchased from Hoechst-Roussel Pharmaceuticals, Somerville, N.J.

Methods—Effects on Lysis of Human Plasma Clots by t-PA

Human plasma clots are formed in micro test tubes by adding 50 μLthrombin (73 NIH unit/mL) to 100 μL human plasma which contains 0.0229μCi 125-iodine labeled fibrinogen. Clot lysis is studied by overlayingthe clots with 50 μL of urokinase or streptokinase (50, 100, or 1000unit/mL) and incubating for 20 hours at room temperature. Afterincubation the tubes are centrifuged in a Beckman Microfuge. 25 μL ofsupernate is added into 1.0 mL volume of 0.03 M tris/0.15 M NaCl bufferfor gamma counting. Counting controls 100 percent lysis are obtained byomitting thrombin (and substituting buffer). The factor Xa inhibitorsare evaluated for possible interference with fibrinolysis by includingthe compounds in the overlay solutions at 1, 5, and 10 μg/mLconcentrations. Rough approximations of IC₅₀ values are estimated bylinear extrapolations from data points to a value which would represent50 percent of lysis for that particular concentration of fibrinolyticagent.

Anticoagulant Activity

Materials

Dog plasma and rat plasma are obtained from conscious mixed-breed hounds(either sex, Butler Farms, Clyde, N.Y., U.S.A.) or from anesthetizedmale Sprague-Dawley rats (Harlan Sprague-Dawley, Inc., Indianapolis,Ind., U.S.A.) by venipuncture into 3.8 percent citrate. Fibrinogen isprepared from in-date ACD human blood as the fraction I-2 according toprevious procedures and specifications. Smith, Biochem. J., 185, 1-11(1980); and Smith, et al., Biochemistry, 11, 2958-2967 (1972). Humanfibrinogen is also purchased as 98 percent pure/plasmin free fromAmerican Diagnostica, Greenwich, Conn. Coagulation reagents Actin,Thromboplastin, Innovin and Human plasma are from Baxter HealthcareCorp., Dade Division, Miami, Fla. Bovine thrombin from Parke-Davis(Detroit, Mich.) is used for coagulation assays in plasma.

Methods

Anticoagulation Determinations

Coagulation assay procedures are as previously described. Smith, et al.,Thrombosis Research, 50, 163-174 (1988). A CoAScreener coagulationinstrument (American LABor, Inc.) is used for all coagulation assaymeasurements. The prothrombin time (PT) is measured by adding 0.05 mLsaline and 0.05 mL Thromboplastin-C reagent or recombinant human tissuefactor reagent (Innovin) to 0.05 mL test plasma. The activated partialthromboplastin time (APTT) is measured by incubation of 0.05 mL testplasma with 0.05 mL Actin reagent for 120 seconds followed by 0.05 mLCaCl₂ (0.02 M). The thrombin time (TT) is measured by adding 0.05 mLsaline and 0.05 mL thrombin (10 NIH units/mL) to 0.05 mL test plasma.The compounds of formula I are added to human or animal plasma over awide range of concentrations to determine prolongation effects on theAPTT, PT, and TT assays. Linear extrapolations are performed to estimatethe concentrations required to double the clotting time for each assay.

Animals

Male Sprague Dawley rats (350-425 gm, Harlan Sprague Dawley Inc.,Indianapolis, Ind.) are anesthetized with xylazine (20 mg/kg, s.c.) andketamine (120 mg/kg, s.c.) and maintained on a heated water blanket (37°C.). The jugular vein(s) is cannulated to allow for infusions.

Arterio-venous Shunt Model

The left jugular vein and right carotid artery are cannulated with 20 cmlengths of polyethylene PE 60 tubing. A 6 cm center section of largertubing (PE 190) with a cotton thread (5 cm) in the lumen, is frictionfitted between the longer sections to complete the arterio-venous shuntcircuit. Blood is circulated through the shunt for 15 min before thethread is carefully removed and weighed. The weight of a wet thread issubtracted from the total weight of the thread and thrombus (see J. R.Smith, Br J Pharmacol, 77:29, 1982).

FeCl₃ Model of Arterial Injury

The carotid arteries are isolated via a midline ventral cervicalincision. A thermocouple is placed under each artery and vesseltemperature is recorded continuously on a strip chart recorder. A cuffof tubing (0.058 ID×0.077 OD×4 mm, Baxter Med. Grade Silicone), cutlongitudinally, is placed around each carotid directly above thethermocouple. FeCl₃ hexahydrate is dissolved in water and theconcentration (20 percent) is expressed in terms of the actual weight ofFeCl₃ only. To injure the artery and induce thrombosis, 2.85 μL ispipetted into the cuff to bathe the artery above the thermocouple probe.Arterial occlusion is indicated by a rapid drop in temperature. The timeto occlusion is reported in minutes and represents the elapsed timebetween application of FeCl₃ and the rapid drop in vessel temperature(see K. D. Kurz, Thromb. Res., 60:269, 1990).

Coagulation Parameters

Plasma thrombin time (TT) and activated partial thromboplastin time(APTT) are measured with a fibrometer. Blood is sampled from a jugularcatheter and collected in syringe containing sodium citrate (3.8percent, 1 part to 9 parts blood). To measure TT, rat plasma (0.1 mL) ismixed with saline (0.1 mL) and bovine thrombin (0.1 mL, 30 U/mL in TRISbuffer; Parke Davis) at 37° C. For APTT, plasma (0.1 mL) and APTTsolution (0.1 mL, Organon Teknika) are incubated for 5 minutes (37° C.)and CaCl₂ (0.1 mL, 0.025 M) is added to start coagulation. Assays aredone in duplicate and averaged.

Index of Bioavailability

Bioavailability studies may be conducted as follows. Compounds areadministered as aqueous solutions to male Fisher rats, intravenously(iv) at 5 mg/kg via tail vein injection and orally (po) to fastedanimals at 20 mg/kg by gavage. Serial blood samples are obtained at 5,30, 120, and 240 minutes postdose following intravenous administrationand at 1, 2, 4, and 6 hours after oral dosing. Plasma is analyzed fordrug concentration using an HPLC procedure involving C8 Bond Elute(Varion) cartridges for sample preparation and a methanol/30 nM ammoniumacetate buffer (pH 4) gradient optimized for each compound. % Oralbioavailability is calculated by the following equation:${\% \quad {Oral}\quad {bioavailability}} = {\frac{{AUC}\quad {po}}{{AUC}\quad {iv}} \times \frac{{Dose}\quad {iv}}{{Dose}\quad {po}} \times 100}$

where AUC is area under the curve calculated from the plasma level ofcompound over the time course of the experiment following oral (AUC po)and intravenous (AUC iv) dosing.

Compounds

Compound solutions are prepared fresh daily in normal saline and areinjected as a bolus or are infused starting 15 minutes before andcontinuing throughout the experimental perturbation which is 15 minutesin the arteriovenous shunt model and 60 minutes in the FeCl₃ model ofarterial injury and in the spontaneous thrombolysis model. Bolusinjection volume is 1 mL/kg for i.v., and 5 mL/kg for p.o., and infusionvolume is 3 mL/hr.

Statistics

Results are expressed as means+/−SEM. One-way analysis of variance isused to detect statistically significant differences and then Dunnett'stest is applied to determine which means are different. Significancelevel for rejection of the null hypothesis of equal means is P<0.05.

Animals

Male dogs (Beagles; 18 months-2 years; 12-13 kg, Marshall Farms, NorthRose, N.Y. 14516) are fasted overnight and fed Purina certifiedPrescription Diet (Purina Mills, St. Louis, Mo.) 240 minutes afterdosing. Water is available ad libitum. The room temperature ismaintained between 66-74° F.; 45-50 percent relative humidity; andlighted from 0600-1800 hours.

Pharmacokinetic Model

Test compound is formulated immediately prior to dosing by dissolving insterile 0.9 percent saline to a 5 mg/mL preparation. Dogs are given asingle 2 mg/kg dose of test compound by oral gavage. Blood samples (4.5mL) are taken from the cephalic vein at 0.25, 0.5, 0.75, 1, 2, 3, 4 and6 hours after dosing. Samples are collected in citrated Vacutainer tubesand kept on ice prior to reduction to plasma by centrifugation. Plasmasamples are analyzed by HPLC MS. Plasma concentration of test compoundis recorded and used to calculate the pharmacokinetic parameters:elimination rate constant, Ke; total clearance, Clt; volume ofdistribution, V_(D); time of maximum plasma test compound concentration,Tmax; maximum concentration of test compound of Tmax, Cmax; plasmahalf-life, t0.5; and area under the curve, A.U.C.; fraction of testcompound absorbed, F.

Canine Model of Coronary Artery Thrombosis

Surgical preparation and instrumentation of the dogs are as described inJackson, et al., Circulation, 82, 930-940 (1990). Mixed-breed hounds(aged 6-7 months, either sex, Butler Farms, Clyde, N.Y., U.S.A.) areanesthetized with sodium pentobarbital (30 mg/kg intravenously, i.v.),intubated, and ventilated with room air. Tidal volume and respiratoryrates are adjusted to maintain blood PO₂, PCO₂, and pH within normallimits. Subdermal needle electrodes are inserted for the recording of alead II ECG.

The left jugular vein and common carotid artery are isolated through aleft mediolateral neck incision. Arterial blood pressure (ABP) ismeasured continuously with a precalibrated Millar transducer (model(MPC-500, Millar Instruments, Houston, Tex., U.S.A.) inserted into thecarotid artery. The jugular vein is cannulated for blood sampling duringthe experiment. In addition, the femoral veins of both hindlegs arecannulated for administration of test compound.

A left thoracotomy is performed at the fifth intercostal space, and theheart is suspended in a pericardial cradle. A 1- to 2-cm segment of theleft circumflex coronary artery (LCX) is isolated proximal to the firstmajor diagonal ventricular branch. A 26-gauge needle-tipped wire anodalelectrode (Teflon-coated, 30-gauge silverplated copper wire) 3-4 mm longis inserted into the LCX and placed in contact with the intimal surfaceof the artery (confirmed at the end of the experiment). The stimulatingcircuit is completed by placing the cathode in a subcutaneous (s.c.)site. An adjustable plastic occluder is placed around the LCX, over theregion of the electrode. A precalibrated electromagnetic flow probe(Carolina Medical Electronics, King, N.C., U.S.A.) is placed around theLCX proximal to the anode for measurement of coronary blood flow (CBF).The occluder is adjusted to produce a 40-50 percent inhibition of thehyperemic blood flow response observed after 10-s mechanical occlusionof the LCX. All hemodynamic and ECG measurements are recorded andanalyzed with a data acquisition system (model M3000, ModularInstruments, Malvern, Pa. U.S.A.).

Thrombus Formation and Compound Administration Regimens

Electrolytic injury of the intima of the LCX is produced by applying100-μA direct current (DC) to the anode. The current is maintained for60 min and then discontinued whether the vessel has occluded or not.Thrombus formation proceeds spontaneously until the LCX is totallyoccluded (determined as zero CBF and an increase in the S—T segment).Compound administration is started after the occluding thrombus isallowed to age for 1 hour. A 2-hour infusion of the compounds of thepresent invention at doses of 0.5 and 1 mg/kg/hour is begunsimultaneously with an infusion of thrombolytic agent (e.g. tissueplasminogen activator, streptokinase, APSAC). Reperfusion is followedfor 3 hour after administration of test compound. Reocclusion ofcoronary arteries after successful thrombolysis is defined as zero CBFwhich persisted for at least 30 minutes.

Hematology and Template Bleeding Time Determinations

Whole blood cell counts, hemoglobin, and hematocrit values aredetermined on a 40-μL sample of citrated (3.8 percent) blood (1 partcitrate:9 parts blood) with a hematology analyzer (Cell-Dyn 900,Sequoia-Turner. Mount View, Calif., U.S.A.). Gingival template bleedingtimes are determined with a Simplate II bleeding time device (OrganonTeknika Durham, N.C., U.S.A.). The device is used to make 2 horizontalincisions in the gingiva of either the upper or lower left jaw of thedog. Each incision is 3 mm wide×2 mm deep. The incisions are made, and astopwatch is used to determine how long bleeding occurs. A cotton swabis used to soak up the blood as it oozes from the incision. Templatebleeding time is the time from incision to stoppage of bleeding.Bleeding times are taken just before administration of test compound (0min), 60 min into infusion, at conclusion of administration of the testcompound (120 min), and at the end of the experiment.

All data are analyzed by one-way analysis of variance (ANOVA) followedby Student—Neuman-Kuels post hoc t test to determine the level ofsignificance. Repeated-measures ANOVA are used to determine significantdifferences between time points during the experiments. Values aredetermined to be statistically different at least at the level ofp<0.05. All values are mean±SEM. All studies are conducted in accordancewith the guiding principles of the American Physiological Society.Further details regarding the procedures are described in Jackson, etal., J. Cardiovasc. Pharmacol., (1993), 21, 587-599.

The following Examples are provided to further describe the inventionand are not to be construed as limitations thereof.

The abbreviations, symbols and terms used in the examples have thefollowing meanings.

Ac=acetyl

aq=aqueous

Bn or Bzl=benzyl

Boc=t-butyloxycarbonyl

Bu=butyl

n-BuLi=butyllithium

Calcd=calculated

conc=concentrated

DMF=dimethylformamide

DMSO=dimethylsulfoxide

eq=(molar) equivalent

Et=ethyl

EtOAc=ethyl acetate

Et₃N=triethylamine

Et₂O=diethyl ether

EtOH=ethanol

FTIR=Fourier transform IR

Hex=hexanes

HPLC=High Performance Liquid Chromatography

HRMS=high resolution mass spectrum

i-PrOH=isopropanol

IR=Infrared Spectrum

LC-MS=liquid chromatography—mass spectrum (using HPLC)

Me=methyl

MeOH=methanol

MS-ES (or ES-MS)=electrospray mass spectrum

MS-FAB (or FAB-MS)=fast atom bombardment mass spectrum

MS-FIA (or FIA-MS)=flow injection analysis mass spectrum

MS-FD (or FD-MS)=field desorption mass spectrum

MS-IS (or IS-MS)=ion spray mass spectrum

NMR=Nuclear Magnetic Resonance

Ph=phenyl

i-Pr=isopropyl

RPHPLC=Reversed Phase High Performance Liquid Chromatography

RT (or Rt)=retention time

satd=saturated

SiO₂=silica gel

SCX=strong cation exchange (resin)

TBS=tert-butyldimethylsilyl

TFA=trifluoroacetic acid

THF=tetrahydrofuran

TIPS=triisopropylsilyl

TLC=thin layer chromatography

tosyl=p-toluenesulfonyl

triflic acid=trifluoromethanesulfonic acid

Unless otherwise stated, pH adjustments and work up are with aqueousacid or base solutions. ¹H-NMR indicates a satisfactory NMR spectrum wasobtained for the compound described. IR (or FTIR) indicates asatisfactory infra red spectrum was obtained for the compound described.

For consistency and clarity, a number of compounds are named assubstituted benzamide derivatives.

Analytical HPLC method was a linear gradient of 90/10 to 50/50 (0.1% TFAin water/0.1% TFA in acetonitrile) over 40 minutes with a flow rate of 1mL/min.

LC-MS Method A: gradient from 50% acetonitrile-40% water-10% water with0.1% trifluoroacetic acid to 90% acetonitrile-10% water with 0.1%trifluoroacetic acid over 5 min; hold 5 min; 0.5 mL/min; Zorbax SB-C₁₈column, 4.6 by 75 mm; 25° C. LC-MS Method B: gradient from 20%acetonitrile-70% water-10% water with 0.1% trifluoroacetic acid to 70%acetonitrile-20% water-10% water with 0.1% trifluoroacetic acid over 5min; hold 5 min; 0.5 mL/min; Zorbax SB-C₁₈ column, 4.6 by 75 mm; 25° C.

EXAMPLE 1 Preparation ofN-(5-Methylpyridin-2-yl)-2-[[1-(4-pyridinyl)piperidin-4-ylcarbonyl]amino]benzamideHydrochloride

A. N-(5-Methylpyridin-2-yl)-2-nitrobenzamide

To a stirring solution of 2-amino-5-methylpyridine (3.1 g, 29 mmol) andpyridine (7.3 mL, 90 mmol) in dichloromethane (200 mL) was added2-nitrobenzoyl chloride (5.7 g, 30 mmol). After 4 h, the solvent wasremoved in vacuo and the residue was partitioned between ethyl acetate(500 mL) and water (250 mL). The organic phase was separated and washedagain with water (250 mL) followed by brine (250 mL) and then dried withMgSO₄, filtered and partially concentrated in vacuo, which resulted inthe formation of a precipitate. After standing overnight, the solid wasfiltered and dried in vacuo to give 3.9 g (52%) of white solid.

¹H-NMR; FD-MS, m/e 256.9 (m); Analysis for C₁₃H₁₁N₃O₃: Calcd: C, 60.70;H, 4.31; N, 16.33; Found: C, 61.21; H, 4.32; N, 16.63.

B. N-(5-Methylpyridin-2-yl)-2-aminobenzamide

To a stirring solution of N-(5-methylpyridin-2-yl)-2-nitrobenzamide (1.5g, 5.8 mmol) and Ni(OAc)₂.4H₂O (2.9 g, 11.7 mmol) in THF (20 mL) andmethanol (40 mL) at 0° C. was added, in small portions, sodiumborohydride (0.88 g, 23.2 mmol). After complete addition and anadditional 5 min, the solvent was evaporated in vacuo and the residuewas partitioned between ethyl acetate (200 mL) and 50% conc NH₄OH (200mL). The organic phase was separated and washed again with 50% concNH₄OH, followed by brine, then dried with MgSO₄, filtered andconcentrated in vacuo to give 1.25 g (95%) of a light yellow solid.

¹H-NMR; FD-MS, m/e 227.1 (m).

C. 1-(4-Pyridinyl)piperidin-4-ylcarbonyl Chloride

To a stirring suspension of 1-(4-pyridinyl)piperidin-4-ylcarboxylic acid(0.8 g, 3.88 mmol) in dichloromethane (75 mL) at reflux was addedthionyl chloride (0.45 mL, 5.82 mmol). After 3 h, the solvent wasremoved in vacuo and the residue was dissolved in dichloromethane (75mL), giving a solution of the title compound, approximately 0.05 M.

D.N-(5-Methylpyridin-2-yl)-2-[[1-(4-pyridinyl)piperidin-4-ylcarbonyl]amino]benzamideHydrochloride

To a stirring solution of N-(5-methylpyridin-2-yl)-2-aminobenzamide(0.28 g, 1.2 mmol) in pyridine (5 mL) and dichloromethane (40 mL) wasadded a solution of 1-(4-pyridinyl)piperidin-4-ylcarbonyl chloride (0.55g, 2.5 mmol) in dichloromethane (40 mL). After stirring overnight, thesolvent was removed in vacuo and the residue was partitioned betweenethyl acetate (300 mL) and 1 N NaOH (150 mL). The organic phase wasseparated and washed again with 1 N NaOH, followed by water and brine,then dried with MgSO₄, filtered and concentrated in vacuo. The residuewas then purified by preparative RPHPLC (C18), eluting with a lineargradient of 90/10 to 50/50 (0.01% HCl/acetonitrile) over 180 min. Thepure product containing fractions were combined and lypholized to give222 mg (40%) of a white powder.

¹H-NMR; FD-MS, m/e 416 (m); Analysis for C₂₄H₂₅N₅O₂.2.1HCl.1.5H₂O:Calcd: C, 55.53; H, 5.84; N, 13.49; Cl, 14.34; Found: C, 55.54; H, 5.79;N, 13.44; Cl, 14.17.

EXAMPLE 2 Preparation ofN-(5-Chloropyridin-2-yl)-2-[[1-(4-pyridinyl)piperidin-4-ylcarbonyl]amino]benzamideHydrochloride

A. N-(5-Chloropyridin-2-yl)-2-nitrobenzamide

Using methods substantially equivalent to those described in example1-A, N-(5-chloropyridin-2-yl)-2-nitrobenzamide (6.5 g, 79%) was preparedfrom 2-amino-5-chloropyridine and 2-nitrobenzoyl chloride.

¹H-NMR; FD-MS, m/e 276.9 (m); Analysis for C₁₂H₈N₃O₃Cl: Calcd: C, 51.91;H, 2.90; N, 15.13; Found: C, 52.61; H, 2.89; N, 15.29.

B. N-(5-Chloropyridin-2-yl)-2-aminobenzamide

To a solution of N-(5-chloropyridin-2-yl)-2-nitrobenzamide (2 g, 7.2mmol) in THF (50 mL) and ethyl acetate (50 mL) was added Raney Ni (0.2g) and the mixture was placed under hydrogen (4.1 bar) in a highpressure apparatus. After shaking overnight, the mixture was filteredand concentrated in vacuo and purified by flash chromatography to give1.5 g (83%) of an off-white solid.

¹H-NMR;

C.N-(5-Chloropyridin-2-yl)-2-[(1-(4-pyridinyl)piperidin-4-ylcarbonyl)amino]benzamideHydrochloride

Using methods substantially equivalent to those described in example1-D,N-(5-chloropyridin-2-yl)-2-[[1-(4-pyridinyl)piperidin-4-ylcarbonyl]amino]benzamidehydrochloride (2.07 g, 69%) was prepared fromN-(5-chloropyridin-2-yl)-2-aminobenzamide and1-(4-pyridinyl)piperidin-4-ylcarbonyl chloride.

¹H-NMR; IS-MS, m/e 436 (m+1); Analysis for C₂₃H₂₂N₅O₂Cl.0.9HCl0.9H₂O:Calcd: C, 56.96; H, 5.13; N, 14.44; Cl, 13.89; Found: C, 57.16; H, 4.75;N, 14.29; Cl, 14.03.

EXAMPLE 3 Preparation ofN-(6-Chloropyridin-3-yl)-2-[[1-(4-pyridinyl)piperidin-4-ylcarbonyl]amino]benzamideHydrochloride

A. N-(6-Chloropyridin-3-yl)-2-nitrobenzamide

Using methods substantially equivalent to those described in example1-A, N-(6-chloropyridin-3-yl)-2-nitrobenzamide (1.24 g, 73%) wasprepared from 2-nitrobenzoyl chloride and 3-amino-6-chloropyridine

¹H-NMR; IS-MS, m/e 278 (m+1); Analysis for C₁₂H₈N₃O₃Cl: Calcd: C, 51.91;H, 2.90; N, 15.13; Found: C, 51.80; H, 3.09; N, 14.98.

B. N-(6-Chloropyridin-3-yl)-2-aminobenzamide

To a stirred solution of N-(6-chloropyridin-3-yl)-2-nitrobenzamide (0.6g, 2.15 mmol) in methanol (150 mL) and tetrahydrofuran (75 mL) was addednickel acetate tetrahydrate (1.07 g, 4.3 mmol). Sodium borohydride(0.326 g, 8.61 mmol) was then added in small portions. After gasevolution had ceased, the solvent was removed in vacuo. The residue waspartitioned between ethyl acetate and concentrated ammonium hydroxide,and the layers separated. The organic phase was washed with concentratedammonium hydroxide and saturated aqueous sodium chloride solution, dried(magnesium sulfate), filtered, and concentrated in vacuo. The solid wassuspended in ether, sonicated, and filtered to give 0.243 g (46%) of apink solid.

¹H-NMR; IS-MS, m/e 248.3 (m+1); Analysis for C₁₂H₁₀N₃OCl: Calcd: C,58.19; H, 4.07; N, 16.96; Found: C, 59.63; H, 4.13; N, 17.27.

C.N-(6-Chloropyridin-3-yl)-2-[[1-(4-pyridinyl)piperidin-4-ylcarbonyl]amino]benzamideHydrochloride

Using methods substantially equivalent to those described in example1-D,N-(6-chloropyridin-3-yl)-2-[[1-(4-pyridinyl)piperidin-4-ylcarbonyl]amino]benzamidehydrochloride (0.12 g, 26%) was prepared fromN-(6-chloropyridin-3-yl)-2-aminobenzamide and1-(4-pyridyl)piperidin-4-ylcarbonyl chloride.

¹H-NMR; IS-MS, m/e 436.2 (m+1); Analysis for C₂₃H₂₂N₅O₂Cl.1.9HCl.2.4H₂O:Calcd: C, 53.96; H, 5.45; N, 13.68; Cl, 13.16; Found: C, 53.97; H, 5.06;N, 13.28; Cl, 13.32.

EXAMPLE 4 Preparation ofN-(5-Chloropyridin-2-yl)-2-[[1-(4-pyridinyl)pyrrolidin-3-yloxycarbonyl]amino]benzamideHydrochloride

A. 1-(4-Pyridinyl)-3-hydroxypyrrolidine

A mixture of 3-hydroxypyrrolidine (9.9 g, 113.64 mmol),4-bromopyridinium hydrochloride (22.098 g, 113.64 mmol), triethylamine(47.5 mL, 341.0 mmol) and 3:1 ethanol:water (150 mL), in a pressure tubereaction vessel, was purged with nitrogen and sealed. The mixture washeated to 150° C. for 96 hours and cooled. The solvent was evaporatedand ethyl acetate (50 mL) was added. After trituration, the organicsolvent was decanted off and saved. Methylene chloride (80 mL) and 2 Nsodium hydroxide (60 mL) were added to the solid. The mixture was shakenvigorously and was filtered with water and methylene chloride wash togive the title compound as an off-white solid. The organic supernatantand the methylene chloride and water washes were combined. This mixturewas extracted with methylene chloride. The organic layer was sodiumsulfate dried and concentrated. The residue was triturated withmethylene chloride and the solid was filtered. This solid was combinedwith the solid from above and vacuum dried (100° C. at 133 Pa for 14hours) to give the title compound as an off-white solid (8.52 g, 46%).

¹H-NMR (300, DMSO-d₆): 8.07 (d, J=6.4 Hz, 1H), 6.44 (d, J=6.4 Hz, 1H),5.01 (br s, 1H), 4.40 (br s, 1H), 3.42-3.20 (m, 3H), 3.12 (d, J=10.6 Hz,1H), 2.07-1.80 (m, 2H).

IS-MS, m/e: 165.4 (m+1).

B.N-(5-Chloropyridin-2-yl)-2-[[1-(4-pyridinyl)pyrrolidin-3-yloxycarbonyl]amino]benzamide

To as solution of 1-(4-pyridinyl)-3-hydroxypyrrolidine (330 mg, 2.01mmol) in dichloromethane (30 mL) was added methanesulfonic acid (0.15mL, 2.31 mmol). After 15 seconds, quinoline (0.3 mL, 2.54 mmol) wasadded, immediately followed by a toluene solution of phosgene (0.65 mL,1.25 mmol). After 5 minutes, the reaction was placed in an oil bath at35° C. After 45 minutes, the reaction was cooled to room temperature.N-(5-Chloropyridin-2-yl)-2-aminobenzamide (498 mg, 2.01 mmol) was added,followed by quinoline (0.3 mL, 2.54 mmol). After stirring overnight, thereaction was diluted with dichloromethane (150 mL) and washed withsaturated aqueous sodium carbonate (2×25 mL). The organic layer wasconcentrated in vacuo and purified by flash column chromatography (100%CH₂Cl₂ to 9% MeOH/CH₂Cl₂) and then by HPLC to give the title product(181 mg, 0.41 mmol, 21%).

¹H-NMR (300 MHz, DMSO-d₆): δ 11.01 (s, 1H); 9.96 (s, 1H); 8.38 (d, J=1.8Hz, 1H); 8.21 (m, 2H); 8.06 (d, J=9.0 Hz, 1H); 7.88 (m, 2H); 7.77 (d,J=8.7 Hz, 1H); 7.51 (t, J=7.2 Hz, 1H); 7.15 (t, J=7.2 Hz, 1H); 6.87 (d,J=7.5 Hz, 1H); 6.80 (d, J=6.6 Hz, 1H); 5.36 (m, 1H); 3.74-3.39 (m, 4H);2.22 (m, 2H).

IS-MS, m/e 438.2 (m+1). Analysis for C₂₂H₂₀N₅O₃Cl.1.0HCl.1.25H₂O: Calcd:C, 53.18; H, 4.77; N, 14.09; Found: C, 53.05; H, 4.64; N, 13.88.

EXAMPLE 5 Preparation ofN-(5-Chloropyridin-2-yl)-2-[(1-benzylpyrrolidin-3-ylmethoxycarbonyl)amino]Benzamide

A. 1-Benzylpyrrolidine-3-methanol

To a mixture of methyl 1-benzylpyrrolidine-3-carboxylate (11.67 g, 50mmol) and tetrahydrofuran, at 0° C. was added lithium aluminum hydride(3.795 g, 100 mmol). The reaction was warmed to room temperature andrefluxed for 24 hours. After cooling to 0° C., the reaction was quenchedwith saturated sodium sulfate and warmed to room temperature.Tetrahyrofuran (50 mL) and solid sodium sulfate were added to themixture. After stirring for 1 hour, the mixture was filtered and thefiltrate was concentrated and vacuum dried for 3 days to give the titlecompound as a colorless oil (8.49 g, 88%).

¹H-NMR (300 MHz, DMSO-d₆): 7.21-7.31 (m, 5H), 4.50 (t, J=5.3 Hz, 1H),3.51 (s, 2H), 3.20-3.31 (m, 2H), 2.35-2.50 (m, 4H), 2.10-2.27 (m, 1H),1.70-1.85 (m, 1H), 1.27-1.43 (m, 1H). IS-MS, m/e: 192.4 (m+1).

B.N-(5-Chloropyridin-2-yl)-2-[(1-benzylpyrrolidin-3-ylmethoxycarbonyl)amino]benzamide

Using methods substantially equivalent to those described in example4-B,N-(5-chloropyridin-2-yl)-2-[(1-benzylpyrrolidin-3-ylmethoxycarbonyl)amino]benzamide(690 mg, 74%) was prepared fromN-(5-chloropyridin-2-yl)-2-aminobenzamide and1-benzylpyrrolidine-3-methanol.

IR (CHCl₃): 1730, 1507, 1375, 1296. ¹H-NMR (400 MHz, DMSO-d₆): δ 10.99(s, 1H); 9.91 (s, 1H); 8.40 (S, 1H); 8.10 (D, J=8.8 Hz, 1H); 7.92 (D,J=9.2 Hz, 1H); 7.87 (D, J=8.01 Hz, 1H); 7.77 (d, J=8.0 Hz, 1H); 7.49 (t,J=7.8 Hz, 1H); 7.27 (m, 5H); 7.13 (t, J=7.6 Hz, 1H); 3.99-3.87 (m, 3H);3.30 (s, 2H); 2.38 (br s, 3H); 2.24 (br s, 1H); 1.82 (br s, 1H); 1.40(br s, 1H). IS-MS, m/e 465.2 (m+1). Analysis for C₂₅H₂₅N₄O₃Cl: Calcd: C,64.58; H, 5.42; N, 12.05; Found: C, 64.35; H, 5.50; N, 12.04.

EXAMPLE 6 Preparation ofN-(5-Chloropyrimidin-2-yl)-2-[[1-(4-pyridinyl)piperidin-4-ylcarbonyl]amino]benzamide

A. N-(5-Chloropyrimidin-2-yl)-2-nitrobenzamide

To a stirred solution of 2-amino-5-chloropyrimidine (2.35 g, 18.14 mmol)in pyridine (10 mL) and dichloromethane (100 mL) was added slowly2-nitrobenzoyl chloride (5.3 mL, 39.90 mmol). After stirring for 2 h,the solvent was removed in vacuo. The residue was partitioned betweenethyl acetate and water, and the layers separated. The organic phase waswashed consecutively with 1 N aqueous citric acid, saturated aqueoussodium chloride, saturated aqueous sodium bicarbonate, and saturatedaqueous sodium chloride, then dried (magnesium sulfate), filtered, andconcentrated in vacuo. The solid was suspended in ether, sonicated, andfiltered to give 4.72 g (61%) of a bis-acylated product (IS-MS, m/e428.1 (m+1).

To a stirring solution of a portion of this material (0.5 g, 1.17 mmol)in p-dioxane (5 mL) was added a solution of lithium hydroxidemonohydrate (0.108 g, 2.58 mmol) in water (3 mL). After stirring for 0.5h, the solvent was removed in vacuo. The residue was washed with THF,then dissolved in water (40 mL) and acidified to pH 3.5 withconcentrated hydrochloric acid which resulted in the formation of aprecipitate. The mixture was filtered and dried to give 0.275 g (84%) ofa tan solid.

¹H-NMR; IS-MS, m/e 279.2 (m+1); Analysis for C₁₁H₇N₄O₃Cl: Calcd: C,47.41; H, 2.53; N, 20.11; Found: C, 47.69; H, 2.55; N, 19.87.

B. N-(5-Chloropyrimidin-2-yl)-2-aminobenzamide

Using methods substantially equivalent to those described in example2-B, N-(5-chloropyrimidin-2-yl)-2-aminobenzamide (0.17 g, 41%) wasprepared from N-(5-chloropyrimidin-2-yl)-2-nitrobenzamide

¹H-NMR; IS-MS, m/e 249.2 (m+1); Analysis for C₁₁H₉N₄OCl: Calcd: C,53.13; H, 3.65; N, 22.53; Found: C, 53.40; H, 3.68; N, 22.64.

C.N-(5-Chloropyrimidin-2-yl)-2-[[1-(4-pyridinyl)piperidin-4-ylcarbonyl]amino]benzamide

Using methods substantially equivalent to those described in example1-D,N-(5-chloropyrimidin-2-yl)-2-[[1-(4-pyridinyl)piperidin-4-ylcarbonyl]amino]benzamide(0.13 g, 30%) was prepared fromN-(5-chloropyrimidin-2-yl)-2-aminobenzamide and1-(4-pyridinyl)piperidin-4-ylcarbonyl chloride. No purification by HPLCwas required.

¹H-NMR; IS-MS, m/e 437.3 (m+1); Analysis for C₂₂H₂₁N₆O₂Cl: Calcd: C,60.48; H, 4.84; N, 19.23; Cl, 8.11; Found: C, 60.41; H, 4.85; N, 19.21;Cl, 8.53.

EXAMPLE 7 Preparation ofN-(6-Chloropyridazin-3-yl)-2-[[1-(4-pyridinyl)piperidin-4-ylcarbonyl]amino]benzamide

A. N-(6-Chloropyridazin-3-yl)-2-nitrobenzamide

Using the procedure described in example 1-A, 3-amino-6-chloropyridazine(5 g, 39 mmol) yielded 8.1 g (75%) of the title compound.

¹H-NMR; FIA-MS, m/e 279.2 (MH+); Analysis for C₁₁H₇ClN₄O₃: Calcd: C,47.41; H, 2.53; N, 20.11. Found: C, 47.23; H, 2.78; N, 20.01.

B.N-(6-Chloropyridazin-3-yl)-2-[[1-(4-pyridyl)piperidin-4-ylcarbonyl]amino]benzamideHydrochloride

Using the procedure described above in example 1-B,N-(6-chloropyridazin-3-yl)-2-nitrobenzamide (2.0 g, 7.18 mmol) yielded0.67 g of crude 2-amino-N-(6-chloropyridazin-3-yl)benzamide, which wastreated with 1-(4-pyridinyl)piperidin-4-ylcarbonyl chloride (436 mg, 1.9mmol) using the procedure described in example 1-D to yield 60 mg (1.8%)of the title compound.

¹H-NMR; FD-MS, m/e 437.2 (M+); Reverse Phase HPLC (1 mL/min, 0.1% TFA inwater/0.1% TFA in acetonitrile, linear gradient 98/2 through 70/30 over45 min)—retention time=32.72 min

EXAMPLE 8 Preparation ofN-(5-Chloropyridin-2-yl)-2-[[1-(4-pyridinyl)piperidin-4-yl]methoxy]benzamideDihyrochloride

A. N-(5-Chloropyridin-2-yl)-2-hydroxybenzamide

Acetylsalicylic acid chloride was prepared from acetylsalicylic acidusing standard oxalyl chloridemethylene chloride conditions. The crudeacid chloride was used without purification to acylate commercial2-amino-5-chloropyridine using standard conditions in methylene chlorideto give 2-acetoxy-N-(5-chloropyridin-2-yl)benzamide in 62% yield as alight yellow solid which was used without purification.

2-Acetoxy-N-(5-chloropyridin-2-yl)benzamide (1.45 g, 5 mmol) wassaponified in aqueous methanolic NaOH. Standard acid-base workup gave1.06 g of crude crystalline product which was recrystallized fromacetone to give N-(5-chloropyridin-2-yl)-2-hydroxybenzamide (0.79 g, 63%yield).

mp 206-207° C.; ¹H-NMR; ES-MS for C₁₂H₉N₂O₂Cl: Calcd: M⁺=248; Found:[M+H]⁺=249; [M−H]⁻=247. Anal for C₁₂H₉N₂O₂Cl: Calcd: C, 57.96; H, 3.65;N 11.27; Found: C, 58.23; H, 3.68; N 11.21.

B.N-(5-Chloropyridin-2-yl)-2-[[1-(4-pyridinyl)piperidin-4-yl]methoxy]benzamideDihyrochloride

1-(4-Pyridinyl)piperidine-4-methanol was prepared using a proceduresimilar to the following: A solution of methylN-(4-pyridinyl)isonipecotate (600 mg, 2.72 mmol) in tetrahydrofuran wasadded to a solution of lithium aluminum hydride (100 mg) intetrahydrofuran (14 mL) cooled to 0° C. Upon consumption of the startingmaterial (0.5-2 h), the mixture was treated with water (0.10 mL), 15%aqueous sodium hydroxide (0.10 mL), and water (0.30 mL). After 0.25 h,the mixture was sonicated for 0.25 h, then poured into a mixture ofethyl acetate, water, sodium tartrate, and potassium tartrate. Theaqueous layer was extracted twice with ethyl acetate and the combinedextracts were dried (magnesium sulfate), filtered, and concentrated invacuo to yield 357 mg (68%) of 1-(4-pyridyl)piperidine-4-methanol, whichwas used without further purification.

¹H-NMR;

N-(5-Chloropyridin-2-yl)-2-hydroxybenzamide (249 mg, 1.0 mmol),[1-(4-pyridinyl)piperidin-4-yl]methanol (192 mg, 1.0 mmol) andtriphenylphosphine (262 mg, 1.0 mmol) were dissolved in 4 mL dry THF and1 mL dry DMF under nitrogen. The solution was cooled to ice-water bathtemperature and a solution of diisopropyl azodicarboxylate (202 mg, 0.20mL, 1.0 mmol) in 2 mL of dry THF was added dropwise over about 45 min.The reaction was allowed to warm to room temperature and stir for 72 h.The solution was evaporated to dryness under vacuum and then dissolvedin ethyl acetate. The ethyl acetate solution was washed with water,dilute aqueous sodium bicarbonate, and brine, and was dried over sodiumsulphate. Evaporation of the solvent under vacuum gave a colorless glasswhich was dissolved in 50 mL of methanol and loaded on two 10 g SCXcolumns. Each column was washed with 150 mL of methanol, and then elutedwith 50 mL of 2 M ammonia in methanol. The methanol/ammonia eluates wereevaporated to driness under vacuum to give 200 mg of off-white solid.This material was purified by reverse phase HPLC to giveN-(5-chloropyridin-2-yl)-2-[[1-(4-pyridinyl)piperidin-4-yl]methoxy]benzamidedihyrochloride as a white solid (151 mg, 30% yield).

¹H-NMR; ES-MS for C₂₃H₂₃N₄O₂Cl: Calcd: M⁺=422; Found: [M+H]⁺=423;[M−H]⁻=421. Anal for C₂₃H₂₅N₄O₂Cl₃: Calcd: C, 55.47; H, 5.06; N 11.25;Found: C, 56.85; H, 4.84; N 11.37.

EXAMPLE 9 Preparation ofN-(5-Chloropyridin-2-yl)-2-[[1-(4-pyridinylmethyl)piperidin-4-ylcarbonyl]amino]benzamide

A.N-(5-Chloropyridin-2-yl)-2-[(1-Boc-piperidin-4-ylcarbonyl)amino]benzamide

To a stirred solution of N-(5-chloropyridin-2-yl)-2-aminobenzamide (0.5g, 1.79 mmol) and Boc-isonipecotic acid (0.41 g, 1.79 mmol) inN,N-dimethylformamide (30 mL) was added1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.69 g,3.58 mmol). After stirring for 15 h, the solvent was removed in vacuo.The residue was partitioned between ethyl acetate and water, and thelayers separated. The organic phase was washed with saturated aqueoussodium chloride, dried (magnesium sulfate), filtered, and concentratedin vacuo. The solid was suspended in ether, sonicated, and filtered togive 0.147 g (18%) of a tan solid.

¹H-NMR; IS-MS, m/e 459.5 (m+1); Analysis for C₂₃H₂₇N₄O₄Cl: Calcd: C,60.19; H, 5.93; N, 12.21; Found: C, 60.04; H, 5.81; N, 12.14.

B. N-(5-Chloropyridin-2-yl)-2-[(piperidin-4-ylcarbonyl)amino]benzamideTrifluoroacetate

To a stirred solution ofN-(5-chloropyridin-2-yl)-2-[(1-Boc-piperidin-4-ylcarbonyl)amino]benzamide(2 g, 4.3 mmol) in dichloromethane (80 mL) and anisole (2.4 mL) wasadded trifluoroacetic acid (8.4 mL, 109 mmol). After stirring for 4 h,the solvent was removed in vacuo. The residue was suspended in ether,sonicated for 0.25 h, stirred vigorously for 15 h, and filtered to give1.93 g (94%) of a white solid.

¹H-NMR; IS-MS, m/e 359.2 (m+1); Analysis for C₂₀H₂₀N₄O₄ClF₃: Calcd: C,50.80; H, 4.26; N, 11.85; F, 12.05; Found: C, 50.74; H, 4.28; N, 11.74;F, 12.34.

C.N-(5-Chloropyridin-2-yl)-2-[[1-(4-pyridinylmethyl)piperidin-4-ylcarbonyl]amino]benzamide

To a solution ofN-(5-chloropyridin-2-yl)-2-[(piperidin-4-ylcarbonyl)amino]benzamidetrifluoroacetate (25 mg, 0.053 mmol) in methanol (0.5 mL) was added4-pyridinecarboxaldehyde (17.1 mg, 0.16 mmol) followed by a solution ofsodium cyanoborohydride (7 mg, 0.106 mmol) in 7.5% acetic acid/methanol(1 mL). After shaking for 15 h, the solution was loaded onto an SCXcolumn, which was pretreated with a solution of 5% acetic acid inmethanol. The column was washed once with methanol and eluted with 2 Nammonia in methanol. The product containing fractions were combined andconcentrated in vacuo. The residue was dissolved in a small amount ofmethanol and a few drops of acetic anhydride were added. After shakingfor 0.5 h, the SCX purification procedure was repeated to give 9.8 mg(41%, 91% pure by HPLC analysis) of the title compound.

IS-MS, m/e 450.1 (m+1); HPLC, Analytical method, RT=18.56 min.

EXAMPLE 10 Preparation ofN-(5-Chloropyridin-2-yl)-2-[[1-(2-furanylmethyl)piperidin-4-ylcarbonyl]amino]benzamide

Using procedures substantially equivalent to those described in example9-C,N-(5-chloropyridin-2-yl)-2-[[1-(2-furanylmethyl)piperidin-4-ylcarbonyl]amino]benzamide(12 mg, 53%, 99% pure by HPLC analysis) was prepared fromN-(5-chloropyridin-2-yl)-2-[(piperidin-4-ylcarbonyl)amino]-benzamidetrifluoroacetate and furan-2-carboxaldehyde

IS-MS, m/e 439.1 (m+1); HPLC Analytical method, RT=24.84 min.

EXAMPLE 11 Preparation ofN-(5-Chloropyridin-2-yl)-2-[(1-benzylpiperidin-4-ylcarbonyl)amino]benzamide

Using procedures substantially equivalent to those described in example9-C,N-(5-chloropyridin-2-yl)-2-[(1-benzylpiperidin-4-ylcarbonyl)amino]benzamide(6.7 mg, 28%, 98% pure by HPLC analysis) was prepared fromN-(5-chloropyridin-2-yl)-2-[(piperidin-4-ylcarbonyl)amino]benzamidetrifluoroacetate and benzaldehyde

FD-MS, m/e 449.1 (m+1); HPLC, Analytical method, RT=27.70 min.

EXAMPLE 12 Preparation ofN-(5-Chloropyridin-2-yl)-2-[[1-(3-pyridinylmethyl)piperidin-4-ylcarbonyl]amino]benzamide

Using procedures substantially equivalent to those described in example9-C,N-(5-chloropyridin-2-yl)-2-[[1-(3-pyridinylmethyl)piperidin-4-ylcarbonyl]amino]benzamide(17 mg, 70%, 98% pure by HPLC analysis) was prepared fromN-(5-chloropyridin-2-yl)-2-[(piperidin-4-ylcarbonyl)amino]-benzamidetrifluoroacetate and pyridine-3-carboxaldehyde

IS-MS, m/e 450.2 (m+1); HPLC, Analytical method, RT=18.87 min.

EXAMPLE 13 Preparation ofN-(5-Chloropyridin-2-yl)-2-[[1-(2-thiazolylmethyl)piperidin-4-ylcarbonyl]amino]benzamide

Using procedures substantially equivalent to those described in example9-C,N-(5-chloropyridin-2-yl)-2-[(1-(2-thiazolylmethyl)piperidin-4-ylcarbonyl)amino]benzamide(7.2 mg, 30%, 88% pure by HPLC analysis) was prepared fromN-(5-chloropyridin-2-yl)-2-[(piperidin-4-ylcarbonyl)amino]-benzamidetrifluoroacetate and thiazole-2-carboxaldehyde

IS-MS, m/e 456.1 (m+1); HPLC, Analytical method, RT 22.74 min.

EXAMPLE 14 Preparation ofN-(5-Chloropyridin-2-yl)-2-[[1-(2-methylpropyl)piperidin-4-ylcarbonyl]amino]benzamide

Using procedures substantially equivalent to those described in example9-C,N-(5-chloropyridin-2-yl)-2-[(1-(2-methylpropyl)piperidin-4-ylcarbonyl)amino]benzamide(17 mg, 78%, 98% pure by HPLC analysis) was prepared fromN-(5-chloropyridin-2-yl)-2-[(piperidin-4-ylcarbonyl)amino]-benzamidetrifluoroacetate and isobutyraldehyde

IS-MS, m/e 415.2 (m+1); HPLC, Analytical method, RT=23.92 min.

EXAMPLE 15 Preparation ofN-(5-Chloropyridin-2-yl)-2-[[1-(2-ethylbutyl)piperidin-4-ylcarbonyl]amino]benzamide

Using procedures substantially equivalent to those described in example9-C,N-(5-chloropyridin-2-yl)-2-[[1-(2-ethylbutyl)piperidin-4-ylcarbonyl]amino]benzamide(14 mg, 59%, 95% pure by HPLC analysis) was prepared fromN-(5-chloropyridin-2-yl)-2-[(piperidin-4-ylcarbonyl)amino]-benzamidetrifluoroacetate and 2-ethylbutyraldehyde

IS-MS, m/e 443.2 (m+1); HPLC, Analytical method, RT=29.94 min.

EXAMPLE 16 Preparation ofN-(5-Chloropyridin-2-yl)-2-[(1-propylpiperidin-4-ylcarbonyl)amino]benzamide

Using procedures substantially equivalent to those described in example9-C,N-(5-chloropyridin-2-yl)-2-[(1-propylpiperidin-4-ylcarbonyl)amino]benzamide(15 mg, 69%, 94% pure by HPLC analysis) was prepared fromN-(5-chloropyridin-2-yl)-2-[(piperidin-4-ylcarbonyl)amino]benzamidetrifluoroacetate and propionaldehyde

IS-MS, m/e 401.1 (m+1); HPLC, Analytical method, RT=22.50 min.

EXAMPLE 17 Preparation ofN-(5-Chloropyridin-2-yl)-2-[(1-cyclopropylmethylpiperidin-4-ylcarbonyl)amino]benzamide

Using procedures substantially equivalent to those described in example9-C,N-(5-chloropyridin-2-yl)-2-[(1-cyclopropylmethylpiperidin-4-ylcarbonyl)amino]benzamide(16 mg, 72%, 97% pure by HPLC analysis) was prepared fromN-(5-chloropyridin-2-yl)-2-[(piperidin-4-ylcarbonyl)amino]-benzamidetrifluoroacetate and cyclopropanecarboxaldehyde

IS-MS, m/e 413.2 (m+1); HPLC, Analytical method, RT=23.38 min.

EXAMPLE 18 Preparation ofN-(5-Chloropyridin-2-yl)-2-[[1-(4-quinolinylmethyl)piperidin-4-ylcarbonyl]amino]benzamide

Using procedures substantially equivalent to those described in example9-C,N-(5-chloropyridin-2-yl)-2-[[1-(4-quinolinylmethyl)piperidin-4-ylcarbonyl]amino]benzamide(13 mg, 52%, 81% pure by HPLC analysis) was prepared fromN-(5-chloropyridin-2-yl)-2-[(piperidin-4-ylcarbonyl)amino]-benzamidetrifluoroacetate and quinoline-4-carboxaldehyde

IS-MS, m/e 500.1 (m+1); HPLC, Analytical method, RT=22.59 min.

EXAMPLE 19 Preparation ofN-(5-Chloropyridin-2-yl)-2-[[1-(2-pyridylmethyl)piperidin-4-ylcarbonyl]amino]benzamide

Using procedures substantially equivalent to those described in example9-C,N-(5-chloropyridin-2-yl)-2-[[1-(2-pyridylmethyl)piperidin-4-ylcarbonyl]amino]benzamide(13 mg, 56%, 100% pure by HPLC analysis) was prepared fromN-(5-chloropyridin-2-yl)-2-[(piperidin-4-ylcarbonyl)amino]-benzamidetrifluoroacetate and pyridine-2-carboxaldehyde

IS-MS, m/e 450.1 (m+1); HPLC, Analytical method, RT=23.35 min.

EXAMPLE 20 Preparation ofN-(5-Chloropyridin-2-yl)-2-[[1-(3-methylbenzyl)piperidin-4-ylcarbonyl]amino]benzamide

Using procedures substantially equivalent to those described in example9-C,N-(5-chloropyridin-2-yl)-2-[[1-(3-methylbenzyl)piperidin-4-ylcarbonyl]amino]benzamide(20 mg, 52%, 100% pure by HPLC analysis) was prepared fromN-(5-chloropyridin-2-yl)-2-[(piperidin-4-ylcarbonyl)amino]-benzamidetrifluoroacetate and 3-methylbenzaldehyde

IS-MS, m/e 463.1 (m+1); HPLC, Analytical method, RT=31.92 min.

EXAMPLE 21 Preparation ofN-(5-Chloropyridin-2-yl)-2-[[1-(2-chlorobenzyl)piperidin-4-ylcarbonyl]amino]benzamide

Using procedures substantially equivalent to those described in example9-C,N-(5-chloropyridin-2-yl)-2-[[1-(2-chlorobenzyl)piperidin-4-ylcarbonyl]amino]benzamide(14 mg, 35%, 98% pure by HPLC analysis) was prepared fromN-(5-chloropyridin-2-yl)-2-[(piperidin-4-ylcarbonyl)amino]-benzamidetrifluoroacetate and 2-chlorobenzaldehyde

IS-MS, m/e 483.1 (m+1); HPLC, Analytical method, RT=30.30 min.

EXAMPLE 22 Preparation ofN-(5-Chloropyridin-2-yl)-2-[(1-(3-chlorobenzyl)piperidin-4-ylcarbonyl]amino]benzamide

Using procedures substantially equivalent to those described in example9-C,N-(5-chloropyridin-2-yl)-2-[[1-(3-chlorobenzyl)piperidin-4-ylcarbonyl]amino]benzamide(23 mg, 56%, 100% pure by HPLC analysis) was prepared fromN-(5-chloropyridin-2-yl)-2-[(piperidin-4-ylcarbonyl)amino]-benzamidetrifluoroacetate and 3-chlorobenzaldehyde

IS-MS, m/e 483.1 (m+1); HPLC, Analytical method, RT=31.07 min.

EXAMPLE 23 Preparation ofN-(5-Chloropyridin-2-yl)-2-[(1-(4-chlorobenzyl)piperidin-4-ylcarbonyl)amino]benzamide

Using procedures substantially equivalent to those described in example9-C,N-(5-chloropyridin-2-yl)-2-[[1-(4-chlorobenzyl)piperidin-4-ylcarbonyl]amino]benzamide(19 mg, 46%, 100% pure by HPLC analysis) was prepared fromN-(5-chloropyridin-2-yl)-2-[(piperidin-4-ylcarbonyl)amino]-benzamidetrifluoroacetate and 4-chlorobenzaldehyde

IS-MS, m/e 483.1 (m+1); HPLC, Analytical method, RT=31.58 min.

EXAMPLE 24 Preparation ofN-(5-Chloropyridin-2-yl)-2-[(1-(4-methoxybenzyl)piperidin-4-ylcarbonyl)amino]benzamide

Using procedures substantially equivalent to those described in example9-C,N-(5-chloropyridin-2-yl)-2-[[1-(4-methoxybenzyl)piperidin-4-ylcarbonyl]amino]benzamide(12 mg, 28%, 97% pure by HPLC analysis) was prepared fromN-(5-chloropyridin-2-yl)-2-[(piperidin-4-ylcarbonyl)amino]-benzamidetrifluoroacetate and 4-methoxybenzaldehyde

IS-MS, m/e 479.1 (m+1); HPLC, Analytical method, RT=29.08 min.

EXAMPLE 25 Preparation ofN-(5-Chloropyridin-2-yl)-2-[[1-(2-ethylbutyl)-3,4-didehydropiperidin-4-ylcarbonyl]amino]benzamide

A. 1-boc-1,2,3,6-Tetrahydro-4-[(trifluoromethyl)sulfonyloxy]pyridine

To a solution of diisopropylamine (38.7 mL, 276 mmol) in tetrahydrofuran(300 mL) at 0° C. under nitrogen was added n-butyllithium (1.6 M inhexane, 172.5 mL, 276 mmol) dropwise via an addition funnel. Afterstirring for 0.5 h, the solution was cooled to −78° C. A solution of1-tert-butoxycarbonyl-4-piperidone (50 g, 251 mmol) in tetrahydrofuran(300 mL) was added. After stirring for 0.5 h, a solution ofN-phenyltrifluoromethanesulfonimide (96 g, 269 mmol) in tetrahydrofuran(300 mL) was added slowly. The reaction was then warmed to 0° C. andafter 3 h, the solvent was removed in vacuo. The residue waschromatographed over alumina, eluting with 5% ethyl acetate in hexanesand the product containing fractions were combined and concentrated invacuo, then dried under high vacuum for 15 h to give 74.84 g (90%) of aclear oil.

¹H-NMR;

B. Methyl 1-boc-1,2,3,6-Tetrahydro-4-pyridinecarboxylate

To a stirred solution of1-Boc-1,2,3,6-tetrahydro-4-[(trifluoromethyl)sulfonyloxy]pyridine (74.84g, 226 mmol) in N,N-dimethylformamide (60 mL) was added triethylamine(4.2 mL, 30.2 mmol), palladium acetate (0.100 g, 0.45 mmol),triphenylphosphine (0. 235 g, 0.9 mmol), and methanol (24.5 mL) and thesolution was placed under an atmosphere of carbon monoxide. Afterstirring for 48 h, the solvent was removed in vacuo. The residue waschromatographed over silica gel, eluting with 5-10% ethyl acetate inhexane. The product containing fractions were combined and concentratedin vacuo to give 2.35 g (65%) of the title compound as a clear oil.

¹H-NMR;

FD-MS, m/e 240.2 (m); Analysis for C₁₂H₁₉NO₄: Calcd: C, 59.74; H, 7.94;N, 5.81; Found: C, 59.60; H, 8.07; N, 5.85.

C. 1-boc-1,2,3,6-Tetrahydro-4-pyridinecarboxylic Acid

To a stirred solution of methyl1-Boc-1,2,3,6-tetrahydro-4-pyridinecarboxylate (2.22 g, 9.2 mmol) inmethanol (10 mL) was added 1.0 N aqueous sodium hydroxide (25 mL). Afterstirring for 2 h, the solvent was removed in vacuo. The residue waspartitioned between diethyl ether and water, and the layers wereseparated. The aqueous phase was acidified to pH 2.5 with concentratedhydrochloric acid and extracted with ethyl acetate. The organic extractwas washed with saturated aqueous sodium chloride, dried (magnesiumsulfate), filtered, and concentrated in vacuo to give 1.62 g (78%) ofthe title compound as a white solid.

¹H-NMR; IS-MS, m/e 226.1 (m−1)⁻; Analysis for C₁₁H₁₇NO₄: Calcd: C,58.14; H, 7.54; N, 6.16; Found: C, 57.41; H, 7.48; N, 6.19.

D.N-(5-Chloropyridin-2-yl)-2-[(1-Boc-3,4-didehydropiperidin-4-ylcarbonyl)amino]benzamide

To a stirred solution of 1-Boc-1,2,3,6-tetrahydro-4-pyridinecarboxylicacid (13.39 g, 58.9 mmol) in tetrahydrofuran (250 mL) was added sodiumethoxide (4.01 g, 58.9 mmol). After stirring for 0.25 h, the solvent wasremoved in vacuo. The residue was suspended in dichloromethane (150 mL);and oxalyl chloride (0.115 mL, 1.32 mmol) was added, followed by acouple drops of N,N-dimethylformamide. After stirring for 0.75 h, thesolvent was removed in vacuo. To the (acid chloride) residue was addeddichloromethane (75 mL) and then a solution ofN-(5-chloropyridine-2-yl)-2 -aminobenzamide (0.245 g, 1.0 mmol) andpyridine (25 mL) in dichloromethane (75 mL). After stirring 15 h, thesolvent was removed in vacuo. The residue was partitioned between ethylacetate and water and the layers separated. The organic phase was washedwith water, saturated aqueous sodium bicarbonate, saturated aqueoussodium chloride, and then dried (magnesium sulfate), filtered, andconcentrated in vacuo. The crude product was chromatographed over silicagel, eluting with a step gradient of 25-40% ethyl acetate in hexane. Theproduct containing fractions were combined and concentrated in vacuo togive 14.65 g (54%) of the title compound as a white solid.

¹H-NMR; IS-MS, m/e 457.4 (m+1); Analysis for C₂₃H₂₅N₄O₄Cl: Calcd: C,60.46; H, 5.51; N, 12.26; Cl, 7.76; Found: C, 61.16; H, 5.60; N, 12.38;Cl, 7.91.

E.N-(5-Chloropyridin-2-yl)-2-[(3,4-didehydropiperidin-4-ylcarbonyl)amino]benzamideTrifluoroacetate

Using methods substantially equivalent to those described in example9-B,N-(5-chloropyridin-2-yl)-2-[(3,4-didehydropiperidin-4-ylcarbonyl)amino]benzamidetrifluoroacetate (0.48 g, 74%) was prepared fromN-(5-chloropyridin-2-yl)-2-[(1-Boc-3,4-didehydropiperidin-4-ylcarbonyl)amino]benzamide

¹H-NMR;

F.N-(5-Chloropyridin-2-yl)-2-[[1-(2-ethylbutyl)-3,4-didehydropiperidin-4-ylcarbonyl]amino]benzamide

Using methods substantially equivalent to those described in example9-C,N-(5-chloropyridin-2-yl)-2-[[1-(2-ethylbutyl)-3,4-didehydropiperidin-4-ylcarbonyl)amino]-benzamide(43 mg, 46%, 98% pure by HPLC analysis) was prepared fromN-(5-chloropyridin-2-yl)-2-[(3,4-didehydropiperidin-4-ylcarbonyl)amino]benzamidetrifluoroacetate and 2-ethylbutyraldehyde

IS-MS, m/e 441.0 (m+1); HPLC, Analytical method, RT=28.63 min.

EXAMPLE 26 Preparation ofN-(5-Chloropyridin-2-yl)-2-[(1-propyl-3,4-didehydropiperidin-4-ylcarbonyl)amino]benzamide

Using methods substantially equivalent to those described in example9-C,N-(5-chloropyridin-2-yl)-2-[(1-propyl-3,4-didehydropiperidin-4-ylcarbonyl)amino]benzamide(30 mg, 36%, 99% pure by HPLC analysis) was prepared fromN-(5-chloropyridin-2-yl)-2-[(3,4-didehydropiperidin-4-ylcarbonyl)amino]benzamidetrifluoroacetate and propionaldehyde

IS-MS, m/e 399.0 (m+1); HPLC, Analytical method, RT=20.63 min.

EXAMPLE 27 Preparation ofN-(5-Chloropyridin-2-yl)-2-[(1-isopropylpiperidin-4-ylcarbonyl)amino]benzamideHydrochloride

To a stirred suspension ofN-(5-chloropyridin-2-yl)-2-[(piperidin-4-ylcarbonyl)amino]benzamidetrifluoroacetate (0.4 g, 0.85 mmol) in acetone (6 mL) and1,2-dichloroethane (10 mL) was added glacial acetic acid (0.2 mL, 3.84mmol) followed by then sodium triacetoxyborohydride (0.81 g, 3.84 mmol).After stirring for 15 h, saturated aqueous ammonium chloride (10 mL) wasadded. After stirring for 0.5 h, the mixture was partitioned betweendichloromethane and water and the layers separated. The organic phasewas washed with saturated aqueous sodium chloride, dried with magnesiumsulfate, filtered, and concentrated in vacuo. The residue was thenpurified by preparative RPHPLC (C18), eluting with a linear gradient of90/10 to 60/40 (0.01% HCl/acetonitrile) over 180 min. The productcontaining fractions were combined and lyophilized to give 0.212 g (57%)of the title compound as a white solid.

¹H-NMR; IS-MS, m/e 401.2 (m+1); Analysis for C₂₁H₂₅N₄O₂Cl.0.9HCl.0.1H₂O:Calcd: C, 57.91; H, 6.04; N, 12.86; Cl, 15.47; Found: C, 57.82; H, 5.95;N, 12.81; Cl, 15.47.

EXAMPLE 28 Preparation ofN-(5-Chloropyridin-2-yl)-2-[(1-isopropyl-3,4-didehydropiperidin-4-ylcarbonyl)amino]benzamideHydrochloride

Using methods substantially equivalent to those described in example 27,N-(5-chloropyridin-2-yl)-2-[(1-isopropyl-3,4-didehydropiperidin-4-ylcarbonyl)amino]-benzamidehydrochloride (0.21 g, 38%) was prepared fromN-(5-chloropyridin-2-yl)-2-[(3,4-didehydropiperidin-4-ylcarbonyl)amino]benzamidetrifluoroacetate and acetone. The preparative RPHPLC (C18) purificationprocedure was elution with a linear gradient of 95/5 to 75/25 (0.01%HCl/acetonitrile) over 180 min.

¹H-NMR; IS-MS, m/e 399.2 (m+1); Analysis for C₂₁H₂₃N₄O₂Cl.1.0HCl.0.7H₂O:Calcd: C, 56.30; H, 5.72; N, 12.51; Cl, 15.83; Found: C, 56.42; H, 5.35;N, 12.11; Cl, 15.99.

EXAMPLE 29 Preparation ofN-(5-Chloropyridin-2-yl)-2-[(1-cyclopentylpiperidin-4-ylcarbonyl)amino]benzamide

Using procedures substantially equivalent to those described in example27,N-(5-chloropyridin-2-yl)-2-[(1-cyclopentylpiperidin-4-ylcarbonyl)amino]benzamide(30 mg, 67%, 99% pure by HPLC analysis) was prepared fromN-(5-chloropyridin-2-yl)-2-[(piperidin-4-ylcarbonyl)amino]-benzamidetrifluoroacetate and cyclopentanone

IS-MS, m/e 427.0 (m+1); HPLC, Analytical method, RT=21.38 min.

EXAMPLE 30 Preparation ofN-(5-Chloropyridin-2-yl)-2-[(1-cyclohexylpiperidin-4-ylcarbonyl)amino]benzamide

Using procedures substantially equivalent to those described in example27,N-(5-chloropyridin-2-yl)-2-[(1-cyclohexylpiperidin-4-ylcarbonyl)amino]benzamide(34 mg, 72%, 97% pure by HPLC analysis) was prepared fromN-(5-chloropyridin-2-yl)-2-[(piperidin-4-ylcarbonyl)amino]-benzamidetrifluoroacetate and cyclohexanone

IS-MS, m/e 441.0 (m+1); HPLC, Analytical method, RT=24.11 min.

EXAMPLE 31 Preparation ofN-(5-chloropyridin-2-yl)-2-[[1-(4-thianyl)-3,4-didehydropiperidin-4-ylcarbonyl)amino]benzamideHydrochloride

Using methods substantially equivalent to those described in example 27,N-(5-chloropyridin-2-yl)-2-[[1-(4-thianyl)-3,4-didehydropiperidin-4-ylcarbonyl)amino]-benzamidehydrochloride (0.26 g, 41%) was prepared fromN-(5-chloropyridin-2-yl)-2-[(3,4-didehydropiperidin-4-ylcarbonyl)amino]benzamidetrifluoroacetate and tetrahydrothiopyran-4-one. The preparative RPHPLCC18) purification procedure was elution with a linear gradient of 90/10to 50/50 (0.01% HCl/acetonitrile) over 180 min.

¹H-NMR; IS-MS, m/e 457.4 (m+1); Analysis for C₂₃H₂₅N₄O₂Cl.1.0HCl.1.2H₂O:Calcd: C, 53.63; H, 5.56; N, 10.88; Cl, 13.77; Found: C, 53.58; H, 5.17;N, 10.77; Cl, 13.57.

EXAMPLE 32 Preparation ofN-(5-Chloropyridin-2-yl)-2-[[1-(1-ethylpropyl)-3,4-didehydropiperidin-4-ylcarbonyl]amino]benzamideHydrochloride

Using methods substantially equivalent to those described in example 27,N-(5-chloropyridin-2-yl)-2-[[1-(1-ethylpropyl)-3,4-didehydropiperidin-4-ylcarbonyl)amino]-benzamidehydrochloride (0.14 g, 24%) was prepared fromN-(5-chloropyridin-2-yl)-2-[(3,4-didehydropiperidin-4-ylcarbonyl)amino]benzamidetrifluoroacetate and 3-pentanone The preparative RPHPLC C18)purification procedure was elution with a linear gradient of 95/5 to75/25 (0.01% HCl/acetonitrile) over 180 min.

¹H-NMR; IS-MS, m/e 427.1 (m+1); Analysis for C₂₃H₂₇N₄O₂Cl.1.5HCl.1.5H₂O:Calcd: C, 54.31; H, 6.24; N, 11.02; Cl, 17.43; Found: C, 53.94; H, 5.61;N, 10.94; Cl, 17.29.

EXAMPLE 33 Preparation ofN-(5-Chloropyridin-2-yl)-2-[[-(1-propylbutyl)-3,4-didehydropiperidin-4-ylcarbonyl]amino]benzamide

Using methods substantially equivalent to those described in example 27,N-(5-chloropyridin-2-yl)-2-[[1-(1-propylbutyl)-3,4-didehydropiperidin-4-ylcarbonyl]amino]-benzamide(5 mg, 10%, 81% pure by HPLC) was prepared fromN-(5-chloropyridin-2-yl)-2-[(3,4-didehydropiperidin-4-ylcarbonyl)amino]benzamidetrifluoroacetate and 4-heptanone

IS-MS, m/e 455.1 (m+1); HPLC, Analytical method, RT=33.28 min.

EXAMPLE 34 Preparation of4-Chloro-N-(5-chloropyridin-2-yl)-2-[[1-(4-pyridinyl)piperidin-4-ylcarbonyl]amino]benzamideHydrochloride

A. 4-Chloro-N-(5-chloropyridin-2-yl)-2-nitrobenzamide

To a stirring suspension of 4-chloro-2-nitrobenzoic acid (20 g, 99 mmol)in dichloromethane (500 mL) was added a few drops of DMF, followed byoxalyl chloride (15.1 g, 119 mmol). After 1 h, the solvent was removedin vacuo and the residue was dissolved in dichloromethane (500 mL). Tothis stirring solution was added pyridine (24 mL, 297 mmol) followed by2-amino-5-chloropyridine (12.7 g, 99 mmol). After stirring overnight,the solvents were removed in vacuo and the residue was stirredvigorously with ethyl acetate and water for several hours. The mixturewas filtered to give a white solid, which was washed with ethyl acetateand dried in vacuo to give 23 g (74%) of the title compound. Thecombined ethyl acetate washings and extract were then washed twice with1 M citric acid, once with brine, twice with saturated aq sodiumbicarbonate, and again with brine. The organic phase was then dried withMgSO₄, filtered and concentrated in vacuo. The solid was then suspendedin diethyl ether, sonicated and filtered to give a second crop of thetitle compound as a white solid (5.79 g, 19%).

¹H-NMR; IS-MS, m/e 312.0 (m); Analysis for C₁₂H₇N₃O₃Cl₂: Calcd: C,46.18; H, 2.26; N, 13.46; Found: C, 46.24; H, 2.37; N, 13.43.

B. 2-Amino-4-chloro-N-(5-chloropyridin-2-yl)benzamide

Using methods substantially equivalent to those described in example2-B, 2-amino-4-chloro-N-(5-chloropyridin-2-yl)benzamide (7.85 g, 87%)was prepared from 4-chloro-N-(5-chloropyridin-2-yl)-2-nitrobenzamide

¹H-NMR; IS-MS, m/e 280.2 (m−1); Analysis for C₁₂H₉N₃OCl₂: Calcd: C,51.09; H, 3.22; N, 14.89; Found: C, 51.52; H, 3.56; N, 14.68.

C.4-Chloro-N-(5-chloropyridin-2-yl)-2-[(1-(4-pyridinyl)piperidin-4-ylcarbonyl)amino]benzamideHydrochloride

Using methods substantially equivalent to those described in example1-D,4-chloro-N-(5-chloropyridin-2-yl)-2-[(1-(4-pyridinyl)piperidin-4-ylcarbonyl)amino]benzamidehydrochloride (0.2 g, 8%) was prepared from2-amino-4-chloro-N-(5-chloropyridin-2-yl)benzamide and1-(4-pyridinyl)piperidin-4-ylcarbonyl chloride. The preparative RPHPLC(C18) purification procedure was elution with a linear gradient of 90/10to 50/50 (0.01% HCl/acetonitrile) over 180 min.

¹H-NMR; IS-MS, m/e 470.2 (m+1); Analysis for C₂₃H₂₁N₅O₂.1.0HCl.0.5H₂O:Calcd: C, 53.55; H, 4.49; N, 13.58; Cl, 20.62; Found: C, 53.75; H, 4.59;N, 13.48; Cl, 20.43.

EXAMPLE 35 Preparation ofN-(5-Chloropyridin-2-yl)-4-fluoro-2-[[1-(4-pyridinyl)piperidin-4-ylcarbonyl]amino]benzamideHydrochloride

A. 4-Fluoro-2-nitrobenzoic Acid

To a stirring solution of KMnO₄ (76 g, 483 mmol) in water (1 L) wasadded 4-fluoro-2-nitrotoluene and the solution was heated to reflux.After 4 h, the hot mixture was filtered and the filtrate was cooled withice, washed with diethyl ether, acidified with conc HCl, and thenextracted twice with diethyl ether. The combined ether extracts werewashed with brine, dried with MgSO₄, filtered and concentrated in vacuoto give 12.07 g (34%) of a white solid.

¹H-NMR; IS-MS, m/e 184.0 (m−1)⁻; Analysis for C₇H₄NO₄F: Calcd: C, 45.42;H, 2.18; N, 7.57; Found: C, 45.63; H, 2.30; N, 7.61.

B. N-(5-Chloropyridin-2-yl)-2-nitro-4-fluorobenzamide

Using methods substantially equivalent to those described in example34-A, N-(5-chloropyridin-2-yl)-4-fluoro-2-nitrobenzamide (16.06 g, 88%)was prepared from 4-fluoro-2-nitrobenzoic acid and2-amino-5-chloropyridine

¹H-NMR; IS-MS, m/e 296.2 (m+1); Analysis for C₁₂H₇N₃O₃ClF: Calcd: C,48.75; H, 2.38; N, 14.21; Found: C, 48.96; H, 2.66; N, 14.40.

C. 2-Amino-N-(5-chloropyridin-2-yl)-4-fluorobenzamide

Using methods substantially equivalent to those described in example2-B, 2-amino-N-(5-chloropyridin-2-yl)-4-fluorobenzamide (7.98 g, 88%)was prepared from N-(5-chloropyridin-2-yl)-4-fluoro-2-nitrobenzamide

¹H-NMR; IS-MS, m/e 264.2 (m−1)⁻; Analysis for C₁₂H₉N₃OClF: Calcd: C,54.25; H, 3.42; N, 15.82; Found: C, 54.45; H, 3.65; N, 15.76.

D.N-(5-Chloropyridin-2-yl)-4-fluoro-2-[[1-(4-pyridinyl)piperidin-4-ylcarbonyl]amino]benzamideHydrochloride

Using methods substantially equivalent to those described in example1-D,N-(5-chloropyridin-2-yl)-4-fluoro-2-[[1-(4-pyridinyl)piperidin-4-ylcarbonyl]amino]benzamidehydrochloride (0.033 g, 2%) was prepared from2-amino-N-(5-chloropyridin-2-yl)-4-fluorobenzamide and1-(4-pyridyl)piperidin-4-ylcarbonyl chloride. The preparative RPHPLC(C18) purification procedure was elution with a linear gradient of 90/10to 50/50 (0.01% HCl/acetonitrile) over 180 min.

¹H-NMR; IS-MS, m/e 454.1 (m+1).

EXAMPLE 36 Preparation of5-Chloro-N-(5-chloropyridin-2-yl)-2-[[1-(4-pyridinyl)piperidin-4-ylcarbonyl]amino]benzamideHydrochloride

A. 5-Chloro-N-(5-chloropyridin-2-yl)-2-nitrobenzamide

Using methods substantially equivalent to those described in example34-A, 5-chloro-N-(5-chloropyridin-2-yl)-2-nitrobenzamide (26.4 g, 85%)was prepared from 2-amino-5-chloropyridine and 5-chloro-2-nitrobenzoicacid.

¹H-NMR; IS-MS, m/e 312.0 (m+1); Analysis for C₁₂H₇N₃O₃Cl₂: Calcd: C,46.18; H, 2.26; N, 13.46; Found: C, 46.37; H, 2.41; N, 13.43.

B. 2-Amino-5-chloro-N-(5-chloropyridin-2-yl)benzamide

Using methods substantially equivalent to those described in example2-B, 2-amino-5-chloro-N-(5-chloropyridin-2-yl)benzamide (7.79 g, 72%)was prepared from 5-chloro-N-(5-chloropyridin-2-yl)-2-nitrobenzamide

¹H-NMR; IS-MS, m/e 282.1 (m+1); Analysis for C₁₂H₉N₃OCl₂: Calcd: C,51.09; H, 3.22; N, 14.89; Cl, 25.13; Found: C, 51.29; H, 3.36; N, 14.89;Cl, 25.41.

C.5-Chloro-N-(5-chloropyridin-2-yl)-2-[[1-(4-pyridinyl)piperidin-4-ylcarbonyl]amino]benzamideHydrochloride

Using methods substantially equivalent to those described in example1-D,5-chloro-N-(5-chloropyridin-2-yl)-2-[[1-(4-pyridinyl)piperidin-4-ylcarbonyl]amino]benzamidehydrochloride was prepared from2-amino-5-chloro-N-(5-chloropyridin-2-yl)benzamide and1-(4-pyridyl)piperidin-4-ylcarbonyl chloride. The preparative RPHPLC(C18) purification procedure was elution with a linear gradient of 90/10to 50/50 (0.01% HCl/acetonitrile) over 180 min.

¹H-NMR; IS-MS, m/e 470.2 (m+1); Analysis forC₂₃H₂₁N₅O₂Cl₂.1.2HCl.0.2H₂O: Calcd: C, 53.36; H, 4.40; N, 13.53; Cl,21.92; Found: C, 53.75; H, 4.65; N, 13.13; Cl, 21.63.

EXAMPLE 37 Preparation ofN-(5-Chloropyridin-2-yl)-5-fluoro-2-[[1-(4-pyridinyl)piperidin-4-ylcarbonyl]amino]benzamideHydrochloride

A. N-(5-Chloropyridin-2-yl)-2-nitro-5-fluorobenzamide

Using methods substantially equivalent to those described in example34-A, N-(5-chloropyridin-2-yl)-5-fluoro-2-nitrobenzamide (8.7 g, 70%)was prepared from 5-fluoro-2-nitrobenzoic acid and2-amino-5-chloropyridine

¹H-NMR; IS-MS, m/e 296.2 (m+1); Analysis for C₁₂H₇N₃O₃ClF: Calcd: C,48.75; H, 2.39; N, 14.21; Found: C, 48.96; H, 2.59; N, 14.02.

B. 2-Amino-N-(5-chloropyridin-2-yl)-5-fluorobenzamide

Using methods substantially equivalent to those described in example2-B, 2-amino-N-(5-chloropyridin-2-yl)-5-fluorobenzamide (11.6 g, 86%)was prepared from N-(5-chloropyridin-2-yl)-5-fluoro-2-nitrobenzamide

¹H-NMR; IS-MS, m/e 264.1 (m−1)⁻; Analysis for C₁₂H₉N₃OClF: Calcd: C,54.25; H, 3.42; N, 15.82; Found: C, 54.46; H, 3.58; N, 15.84.

C.N-(5-Chloropyridin-2-yl)-5-fluoro-2-[[1-(4-pyridinyl)piperidin-4-ylcarbonyl]amino]benzamideHydrochloride

Using methods substantially equivalent to those described in example1-D,N-(5-chloropyridin-2-yl)-5-fluoro-2-[[1-(4-pyridinyl)piperidin-4-ylcarbonyl]amino]benzamidehydrochloride (0.47 g, 21%) was prepared from2-amino-N-(5-chloropyridin-2-yl)-5-fluorobenzamide and1-(4-pyridyl)piperidin-4-ylcarbonyl chloride. The preparative RPHPLC(C18) purification procedure was elution with a linear gradient of 90/10to 50/50 (0.01% HCl/acetonitrile) over 180 min.

¹H-NMR; IS-MS, m/e 454.0 (m+1); Analysis forC₂₃H₂₁N₅O₂Cl₂F.1.0HCl.0.3H₂O: Calcd: C, 55.72; H, 4.59; N, 14.13; Cl,14.30; Found: C, 55.69; H, 4.66; N, 13.82; Cl, 14.39.

EXAMPLE 38 Preparation ofN-(5-Chloropyridin-2-yl)-2-[(1-cyclohexyl-3,4-didehydropiperidin-4-ylcarbonyl)amino]benzamideHydrochloride

Using methods substantially equivalent to those described in example 27,N-(5-chloropyridin-2-yl)-2-[(1-cyclohexyl-3,4-didehydropiperidin-4-ylcarbonyl)amino]-benzamidehydrochloride (0.176 g, 29%) was prepared fromN-(5-chloropyridin-2-yl)-2-[(3,4-didehydropiperidin-4-ylcarbonyl)amino]benzamidetrifluoroacetate and cyclohexanone The preparative RPHPLC (C18)purification procedure was elution with a linear gradient of 95/5 to70/30 (0.01% HCl/acetonitrile) over 200 min.

¹H-NMR; IS-MS, m/e 439.2 (m+1).

EXAMPLE 39 Preparation ofN-(5-Chloropyridin-2-yl)-2-[[1-(tetrahydro-pyran-4-yl)-3,4-didehydropiperidin-4-ylcarbonyl)amino]-benzamideHydrochloride

Using methods substantially equivalent to those described in example 27,N-(5-chloropyridin-2-yl)-2-[[1-(tetrahydro-pyran-4-yl)-3,4-didehydropiperidin-4-ylcarbonyl)amino]benzamidehydrochloride was prepared fromN-(5-chloropyridin-2-yl)-2-[(3,4-didehydropiperidin-4-ylcarbonyl)amino]benzamidetrifluoroacetate and tetrahydro-4H-pyran-4-one. The preparative RPHPLC(C18) purification procedure was elution with a linear gradient of 95/5to 70/30 (0.01% HCl/acetonitrile) over 200 min.

¹H-NMR; IS-MS, m/e 441.2 (m+1); Analysis for C₂₃H₂₅N₄O₃Cl.1.0HCl.0.2H₂O:Calcd: C, 57.43; H, 5.53; N, 11.65; Cl, 14.74; Found: C, 57.31; H, 5.43;N, 11.58; Cl, 15.09.

EXAMPLE 40 Preparation ofN-(5-Chloropyridin-2-yl)-2-(4-phenylbenzoylamino)benzamide

To a solution of N-(5-chloropyridin-2-yl)-2-aminobenzamide(0.247 g, 1mmol) in dichloromethane (10 mL) and pyridine (0.5 mL) was added asolution of 4-biphenylcarbonyl chloride (0.217 g, 1 mmol) indichloromethane (5 mL). After stirring overnight the solvent was removedin vacuo. The residue was partitioned between ethyl acetate (50 mL) andwater (25 mL). Separate the layers and wash the organic layer with water(2×10 mL), saturated sodium bicarbonate (2×20 mL), hydrochloric acid(0.2 N, 1×20 mL). Dried over MgSO₄, filtered and concentrated in vacuo.The residue was then purified by RPHPLC (30% ethyl acetate/hexane) togive 0.4 g (94%) of pure product.

¹H-NMR; FD-MS m/e 426.1 (m−); Analysis for C₂₅H₁₈N₃O₂Cl: Calcd: C,70.18; H, 4.24; N, 9.82; Found: C, 70.11; H, 4.26; N, 9.87.

EXAMPLE 41 Preparation ofN-(5-Chloropyridin-2-yl)-5-fluoro-2-[(1-isopropyl-3,4-didehydropiperidin-4-ylcarbonyl)amino]-benzamideHydrochloride

A.N-(5-Chloropyridin-2-yl)-2-[(1-Boc-3,4-didehydropiperidin-4-ylcarbonyl)amino]-5-fluorobenzamide

Using methods substantially equivalent to those described in example25-D,N-(5-chloropyridin-2-yl)-2-[(1-Boc-3,4-didehydropiperidin-4-ylcarbonyl)amino]-5-fluorobenzamide(1.32 g, 67%) was prepared from2-amino-N-(5-chloropyridin-2-yl)-5-fluorobenzamide

¹H-NMR;

B.N-(5-Chloropyridin-2-yl)-5-fluoro-2-[(3,4-didehydropiperidin-4-ylcarbonyl)amino]benzamideTrifluoroacetate

Using methods substantially equivalent to those described in example9-B,N-(5-chloropyridin-2-yl)-5-fluoro-2-[(3,4-didehydropiperidin-4-ylcarbonyl)amino]benzamidetrifluoroacetate (1.07 g, 80%) was prepared fromN-(5-chloropyridin-2-yl)-2-[(1-Boc-3,4-didehydropiperidin-4-yl-carbonyl)amino]-5-fluorobenzamide

¹H-NMR; IS-MS, m/e 375.0 (m+1);

C.N-(5-Chloropyridin-2-yl)-5-fluoro-2-[(1-isopropyl-3,4-didehydropiperidin-4-ylcarbonyl)amino]benzamideHydrochloride

Using methods substantially equivalent to those described in example 27,N-(5-chloropyridin-2-yl)-5-fluoro-2-[(1-isopropyl-3,4-didehydropiperidin-4-ylcarbonyl)amino]-benzamidehydrochloride (0.255 g, 56%) was prepared from acetone andN-(5-chloropyridin-2-yl)-5-fluoro-2-[(3,4-didehydropiperidin-4-ylcarbonyl)amino]benzamidetrifluoroacetate. The preparative RPHPLC (C18) purification procedurewas elution with a linear gradient of 90/10 to 50/50 (0.01%HCl/acetonitrile) over 180 min.

¹H-NMR; IS-MS, m/e 417.2 (m+1); Analysis forC₂₁H₂₂N₄O₂ClF.1.1HCl.1.3H₂O: Calcd: C, 52.50; H, 5.39; N, 11.66; Cl,15.50; Found: C, 52.53; H, 5.16; N, 11.59; Cl, 15.47.

EXAMPLE 42 Preparation ofN-(5-Chloropyridin-2-yl)-5-fluoro-2-[(1-isopropylpiperidin-4-ylcarbonyl)amino]benzamideHydrochloride

A.N-(5-Chloropyridin-2-yl)-2-[(1-Boc-piperidin-4-ylcarbonyl)amino]-5-fluorobenzamide

Using methods substantially equivalent to those described in example25-D,N-(5-chloropyridin-2-yl)-2-[(1-Boc-piperidin-4-ylcarbonyl)amino]-5-fluorobenzamide(2.15 g, 92%) was prepared from2-amino-N-(5-chloropyridin-2-yl)-5-fluorobenzamide

IS-MS, m/e 477.0 (m+1).

B.N-(5-Chloropyridin-2-yl)-5-fluoro-2-[(piperidin-4-ylcarbonyl)amino]benzamideTrifluoroacetate

Using methods substantially equivalent to those described in example9-B,N-(5-chloropyridin-2-yl)-5-fluoro-2-[(piperidin-4-ylcarbonyl)amino]benzamidetrifluoroacetate (1.7 g, 92%) was prepared fromN-(5-chloropyridin-2-yl)-2-[(1-Boc-piperidin-4-ylcarbonyl)amino]-5-fluorobenzamide

¹H-NMR; IS-MS, m/e 377.0 (m+1).

C.N-(5-Chloropyridin-2-yl)-5-fluoro-2-[(1-isopropylpiperidin-4-ylcarbonyl)amino]benzamideHydrochloride

Using methods substantially equivalent to those described in example 27,N-(5-chloropyridin-2-yl)-5-fluoro-2-[(1-isopropylpiperidin-4-ylcarbonyl)amino]benzamidehydrochloride (0.264 g, 58%) was prepared fromN-(5-chloropyridin-2-yl)-5-fluoro-2-[(piperidin-4-ylcarbonyl)amino]-benzamidetrifluoroacetate and acetone. The preparative RPHPLC (C18) purificationprocedure was elution with a linear gradient of 90/10 to 50/50 (0.01%HCl/acetonitrile) over 180 min.

¹H-NMR; IS-MS, m/e 419.2 (m+1); Analysis forC₂₁H₂₄N₄O₂ClF.1.1HCl.1.4H₂O: Calcd: C, 52.09; H, 5.81; N, 11.57; Cl,15.38; Found: C, 52.11; H, 5.61; N, 11.32; Cl, 15.38.

EXAMPLE 43 Preparation of5-Chloro-N-(5-chloropyridin-2-yl)-2-[(1-isopropyl-3,4-didehydropiperidin-4-ylcarbonyl)amino]-benzamideHydrochloride

A.N-(5-Chloropyridin-2-yl)-2-[(1-Boc-piperidin-3-ene-4-ylcarbonyl)amino]-5-chlorobenzamide

Using methods substantially equivalent to those described in example25-D,N-(5-chloropyridin-2-yl)-2-(1-Boc-3,4-didehydropiperidin-4-ylcarbonyl)amino]-5-chlorobenzamide(2.14 g, 99%) was prepared fromN-(5-chloropyridin-2-yl)-2-amino-5-chlorobenzamide

¹H-NMR; IS-MS, m/e 490.9 (m+1).

B.N-(5-Chloropyridin-2-yl)-2-[(3,4-didehydropiperidin-4-ylcarbonyl)amino]-5-chlorobenzamideTrifluoroacetate

Using methods substantially equivalent to those described in example9-B,N-(5-chloropyridin-2-yl)-2-[(3,4-didehydropiperidin-4-ylcarbonyl)amino]-5-chlorobenzamidetrifluoroacetate (1.28 g, 58%) was prepared fromN-(5-chloropyridin-2-yl)-2-[(1-Boc-3,4-didehydropiperidin-4-ylcarbonyl)amino]-5-chlorobenzamide

¹H-NMR; IS-MS, m/e 390.9 (m+1).

C.5-Chloro-N-(5-chloropyridin-2-yl)-2-[(1-isopropyl-3,4-didehydropiperidin-4-ylcarbonyl)amino]benzamideHydrochloride

Using methods substantially equivalent to those described in example 27,5-chloro-N-(5-chloropyridin-2-yl)-2-[(1-isopropyl-3,4-didehydropiperidin-4-ylcarbonyl)amino]-benzamidehydrochloride (0.172 g, 38%) was prepared fromN-(5-chloropyridin-2-yl)-2-[(3,4-didehydropiperidin-4-ylcarbonyl)amino]-5-chlorobenzamidetrifluoroacetate and acetone. The preparative RPHPLC C18) purificationprocedure was elution with a linear gradient of 90/10 to 50/50 (0.01%HCl/acetonitrile) over 180 min.

¹H-NMR; IS-MS, m/e 433.1 (m+1); Analysis forC₂₁H₂₂N₄O₂Cl₂.1.5HCl.0.5H₂O: Calcd: C, 50.74; H, 4.97; N, 11.27; Cl,24.97; Found: C, 50.72; H, 4.72; N, 11.19; Cl, 25.25.

EXAMPLE 44 Preparation of5-Chloro-N-(5-chloropyridin-2-yl)-2-[(1-isopropylpiperidin-4-ylcarbonyl)amino]benzamideHydrochloride

A.N-(5-Chloropyridin-2-yl)-2-[(1-Boc-piperidin-4-ylcarbonyl)amino]-5-chlorobenzamide

Using methods substantially equivalent to those described in example25-D,N-(5-chloropyridin-2-yl)-2-[(1-Boc-piperidin-4-ylcarbonyl)amino]-5-chlorobenzamide(2.8 g, 72%) was prepared from2-amino-5-chloro-N-(5-chloropyridin-2-yl)benzamide and1-Boc-piperidin-4-ylcarbonyl chloride.

¹H-NMR; IS-MS, m/e 493.0 (m+1).

B.5-Chloro-N-(5-chloropyridin-2-yl)-2-[(piperidin-4-ylcarbonyl)amino]benzamideTrifluoroacetate

Using methods substantially equivalent to those described in example9-B,5-chloro-N-(5-chloropyridin-2-yl)-2-[(piperidin-4-ylcarbonyl)amino]benzamidetrifluoroacetate (2.07 g, 95%) was prepared fromN-(5-chloropyridin-2-yl)-2-[(1-Boc-piperidin-4-ylcarbonyl)amino]-5-chlorobenzamide

¹H-NMR; IS-MS, m/e 392.9 (m+1).

C.5-Chloro-N-(5-chloropyridin-2-yl)-2-[(1-isopropylpiperidin-4-ylcarbonyl)amino]benzamideHydrochloride

Using methods substantially equivalent to those described in example 27,5-chloro-N-(5-chloropyridin-2-yl)-2-[(1-isopropylpiperidin-4-ylcarbonyl)amino]benzamidehydrochloride (0.103 g, 22%) was prepared from5-chloro-N-(5-chloropyridin-2-yl)-2-[(piperidin-4-ylcarbonyl)amino]-benzamidetrifluoroacetate. The preparative RPHPLC (C18) purification procedurewas elution with a linear gradient of 90/10 to 50/50 (0.01%HCl/acetonitrile) over 180 min.

¹H-NMR; IS-MS, m/e 435.3 (m+1); Analysis forC₂₁H₂₄N₄O₂Cl₂.1.2HCl.0.5H₂O: Calcd: C, 51.67; H, 5.41; N, 11.48; Cl,23.24; Found: C, 51.52; H, 5.31; N, 11.55; Cl, 23.35.

An alternative preparation for the title compound is as follows:

D. Ethyl 1-Isopropylpiperidine-4-carboxylate

An autoclave was charged with ethyl isonipecotate (50 g, 318.0 mmol),10% Pd/C (5 g, 10 wt %), acetone (450 mL, 6.13 mol) and ethanol (100mL). The autoclave was pressurized to 4.1 bar with H₂, and the slurrywas heated to 35° C. After 14 h the mixture was filtered, rinsed withacetone, and was concentrated to remove excess acetone. The crudematerial was taken on without any purification:

¹H-NMR (500 MHz, CDCl₃) δ 4.11 (q, J=7.1 Hz, 2H), 2.84 (m, 2H), 2.68(hep, J=6.4 Hz, 1H), 2.23 (m, 1H), 2.14 (m, 2H), 1.89 (m, 2H), 1.72 (m,2H), 1.24 (t, J=7.1 Hz, 3H), 1.01 (d, J=6.6 Hz, 6H).

E. 1-Isopropylpiperidine-4-carboxylic Acid

Crude ethyl 1-isopropylpiperidine-4-carboxylate (63.39 g, 318.0 mmol)was dissolved in ethanol (500 mL), and NaOH (25.3 g, 632 mmol) wasadded. The solution was heated to reflux for 15.75 h at which point itwas allowed to cool to 34° C. A solution of ethanolic HCl (220 mL, 2.9 Msolution) was added rapidly which caused a mild exotherm and immediateprecipitation. The resulting NaCl was filtered using a fritted funnel,and the cloudy filtrate was refiltered through diatomaceous earth. Thefiltrate was concentrated and dissolved in 50% EtOAc/EtOH (600 mL) andheated on a steam bath. The insoluble material was removed by afiltration through diatomaceous earth, and the resulting filtrate wasconcentrated to a solid which was dried in a 50° C. vacuum oven to yield54.09 g of yellow solid (corrected for 0.2 wt % EtOH by ¹H-NMR analysis)which is a 99% yield over two steps. No further purification wasattempted:

¹H-NMR (500 MHz, MeOD-d₆) δ 3.49 (hep, J=6.6 Hz, 1H), 3.41 (m, 2H), 3.06(m, 2H), 2.40 (m, 1H), 2.14 (m, 2H), 1.96 (m, 2H), 1.37 (d, J=6.6 Hz,6H); ¹³C NMR (75 MHz, MeOD-d₄) 181.2, 59.4, 42.8, 28.4, 17.4 ppm; MS(electrospray) m/z 172.2 (MH+), 154.1, 130.1, 112.2.

F.5-Chloro-N-(5-chloropyridin-2-yl)-2-[(1-isopropylpiperidin-4-ylcarbonyl)amino]benzamide

A slurry of 1-isopropylpiperidine-4-carboxylic acid (501.0 mg, 2.92mmol) and 50% DMF/THF (6.3 mL) was cooled in an ice bath, and a solutionof iso-butyl chloroformate (0.34 mL, 2.63 mmol) and 50% DMF/THF (0.7 mL)was added over 10 min via syringe. The ice bath was removed ataddition's end, and the mixture was allowed to warm to ambienttemperature. After 1 h,2-amino-5-chloro-N-(5-chloropyridin-2-yl)benzamide (414.8 mg, 1.47 mmol)was added in one portion, and the slurry was heated to 70° C. in an oilbath. Analysis by HPLC after 17 h showed only 2.5% of unacylated amineremained, so the volatiles were removed under reduced pressure, andEtOAc (25 mL) and water (20 mL) were added. The organic layer wasextracted with saturated NaHCO₃ (2×20 mL), and the combined aqueouslayers were back-extracted with CH₂Cl₂ (2×20 mL). The combined organiclayers were dried (Na₂SO₄), filtered and concentrated to 0.97 g ofyellow solid which was found to be contaminated with 45 wt % DMF.Corrected yield was 0.53 g (83% yield), and no further purification wasperformed:

¹H-NMR (500 MHz, CDCl₃) δ 10.72 (s, 1H), 8.70 (s, 1H), 8.66 (d, J=9.2Hz, 1H), 8.26 (m, 2H), 7.75 (dd, J=8.9, 2.7 Hz, 1H), 7.62 (d, J=2.5 Hz,1H), 7.47 (dd, J=8.9, 2.5 Hz, 1H), 2.96 (m, 2H), 2.74 (hep, J=6.4 Hz,1H), 2.30-2.19 (m, 3H), 2.00 (m, 2H), 1.82 (m, 2H), 1.05 (d, J=6.6 Hz,6H).

G.5-Chloro-N-(5-chloropyridin-2-yl)-2-[(1-isopropylpiperidin-4-ylcarbonyl)amino]benzamideHydrochloride

A solution of ethereal HCl (1.5 mL, 1 M solution) was added rapidly to asolution of the above crude free base (0.53 g, 1.2 mmol) and CH₂Cl₂ (16mL) at 23° C. Precipitation occurred during the addition, and afterstirring the resulting slurry for 5 min, Et₂O (12 ml,) was added. Theslurry was cooled in an ice bath for 30 min, at which point it wasfiltered, and the cake was washed with copious ether to rinse anyresidual DMF away. The product was dried in a 50° C. vacuum oven toprovide 547.9 mg of the title compound as a white solid (97%) whichcontained 4 wt % H₂O by proton NMR analysis:

¹H-NMR (500 MHz, DMSO-d₆, 3.2:1 mixture of conformational isomers) δ11.14 (s, 0.8H), 11.06 (s, 0.2H), 10.64 (m, 0.2H), 10.44 (m, 1H), 10.32(m, 0.8H), 8.43 (d, J=2.7 Hz, 0.8H), 8.41 (d, J=2.7 Hz, 0.2H), 8.11 (d,J=8.9 Hz, 1H), 7.98-7.91 (m, 1.8H), 7.78 (d, J=2.5 Hz, 0.8H), 7.65 (d,J=2.1 Hz, 0.2H), 7.59-7.53 (m, 1.2H), 3.36 (m, 2.4H), 3.26 (m, 0.3H),3.11 (m, 0.5H), 2.93 (m, 2.4H), 2.64 (m, 0.8H), 2.49 (m, 0.3H), 2.18 (m,0.5H), 2.03 (m, 3.6H), 1.25 (d, J=6.6 Hz, 4.8H), 1.11 (d, J=6.6 Hz,1.2H); ¹³C NMR (63 MHz, DMSO-d₆, mixture of conformational isomers)172.3, 171.8, 166.0, 150.9, 150.5, 146.4, 137.8, 136.0, 134.7, 131.4,130.8, 130.0, 128.9, 128.0, 127.5, 126.8, 125.9, 125.5, 124.2, 116.2,115.6, 57.0, 56.4, 46.9, 44.7, 35.0, 25.4, 24.0, 16.3, 16.0 ppm; IR(KBr) 1301, 1373, 1458, 1512, 1664, 3233 cm⁻¹; MS (electrospray) m/z 433(M−H).

EXAMPLE 45 Preparation ofN-(5-Chloropyridin-2-yl)-2-[[4-(4-pyridinyl)piperazin-1-ylmethylcarbonyl]amino]benzamide

A. 2-(Bromoacetyl)amino-N-(5-chloropyridin-2-yl)benzamide

To a stirred solution of 2-amino-N-(5-chloropyridin-2-yl)benzamide (1.65g, 6.66 mmol) in tetrahydrofuran (60 mL)and diisopropylethyl amine (1.28mL) was added bromoacetyl bromide (0.64 mL, 7.32 mmol) dropwise at 0° C.The reaction mixture was warmed to room temperature and stirredovernight. Diluted the reaction mixture with ethyl acetate (120 mL) andwater (50 mL). Separated the organic layer and washed with water (25mL), saturated sodium bicarbonate (50 mL), 0.2 N hydrochloric acid (25mL), water (50 mL). Dried over sodium sulfate and remove the solvent toget crude product (2.2 g), which was used as such in the following step.

B.N-(5-Chlorpyridin-2-yl)-2-[[4-(4-pyridinyl)piperazin-1-ylmethylcarbonyl]amino]benzamide

To a solution of 2-(bromoacetyl)amino-N-(5-chloropyridin-2-yl)benzamide(0.369 g, 1 mmol) in dichloromethane (10 ml) was added potassiumcarbonate (0.169 g, 1.22 mmol) and 1-(4-pyridyl)piperazine (0.171 mg,1.05 mmol). The reaction was stirred overnight at room temperature.Water (2 mL) was added and the mixture was passed through a column offlux-calcined, high purity, inert diatomaceous earth packed into apolypropylene tube (article number CE 1103 from Varian) to remove water.The solvent was removed and the residue was purified by RPHPLC(CH₂Cl₂/5% 2 N ammonia in methanol) to give 0.08 g of pure titleproduct.

¹H-NMR; FD-MS, m/e 451.0 (m+1).

EXAMPLE 46 Preparation of2-(4-tert-Butylbenzoylamino)-N-(5-chloropyridin-2-yl)benzamide

A. Methyl 2-(4-tert-butylbenzoylamino)benzoate

To a stirring solution of methyl 2-aminobenzoate (5 g, 33.1 mmol) andpyridine (5.3 g, 66 mmol) in dichloromethane (100 mL) was added4-dimethylaminopyridine (0.2 g, 1.6 mmol). The mixture was cooled to 0°C. and treated with 4-tert-butylbenzoyl chloride (6.5 g, 33.1 mmol).After stirring overnight, the reaction mixture was diluted withdichloromethane (100 mL)and washed twice with 1 M aqueous citric acid(100 mL). The organic layer was then washed sequentially with water (100mL) and 5 N aqueous HCl. It was dried over MgSO₄, filtered andconcentrated in vacuo to give 10.68 g (quantitative) of a colorless oil.

¹H-NMR; FD-MS, m/e 312 (m+1); Analysis for C₁₉H₂₁NO₃: Calcd: C, 73.29;H, 6.80; N, 4.50; Found: C, 73.09; H, 6.86; N, 5.33.

B. 2-(4-tert-Butylbenzoylamino)benzoic Acid

A stirring solution of methyl 2-(4-tert-butylbenzoylamino)benzoate (10.4g, 33.4 mmol) and THF (200 mL) was treated with 1 M aqueous lithiumhydroxide (40 mL) and methanol (80 mL). After stirring over night atroom temperature, the mixture was treated with 1 M aqueous HCl (40 mL)and the solvent was removed in vacuo. The residue was partitionedbetween ethyl acetate (400 mL) and brine (100 mL). The organic phase wasseparated, then dried with MgSO₄, filtered and concentrated in vacuo togive 9.69 g (98%) of a white powder.

¹H-NMR; IS-MS, m/e 296 (m−1); Analysis for C₁₈H₁₉NO₃: Calcd: C, 72.71;H, 6.44; N, 4.71; Found: C, 71.04; H, 6.59; N, 6.13.

C. 2-(4-tert-Butylphenyl)-4H-3,1-benzoxazin-4-one

To a stirring mixture of the 2-(4-tert-butylbenzoylamino)benzoic acid(9.5 g, 32 mmol), CH₂Cl₂ (200 mL) and 2 drops of DMF was added 2 Moxalyl chloride in CH₂Cl₂ (19 mL). After stirring at ambient temperaturefor 45 minutes, the mixture was concentrated under vacuum to an oil,redissolved in 100 mL CH₂Cl₂ and cooled to 0° C. To this was addedtriethylamine (3.3 g, 33 mmol) at 0° C. for 1 hour. The solvent wasremoved in vacuo and the residue purified by flash chromatrography usinghexanes/EtOAc to give 8.6 g (96%) of a white powder.

¹H-NMR; IS-MS, m/e 280 (m+1).

D. N-(5-Chloropyridin-2-yl)-2-(4-tert-butylbenzoylamino)benzamide

A mixture of the above benzoxazinone (55 mg, 0.2 mmol),2-amino-5-chloropyridine (55 mg, 0.43 mmol), KCN (100 mg, 1.54 mmol) and2 mL of DMF was heated at 100° C. for 4 hours. The mixture was treatedwith brine (25 mL) and extracted with EtOAc (2×25 mL). The extracts werewashed with brine (2×100 mL), dried over MgSO₄ and concentrated todryness in vacuo. The residue was purified by radial chromatographyusing hexanes/EtOAc to give 35 mg (43%) of a white solid.

¹H-NMR; FD-MS, m/e 408 (m+1); Analysis for C₂₃H₂₂ClN₃O₂: Calcd: C,67.73; H, 5.44; N, 10.30; Found: C, 67.53; H, 5.87; N, 10.60.

EXAMPLE 47 Preparation ofN-(5-Chloropyridin-2-yl)-2-(piperidin-4-ylmethylamino)benzamide

A. 1-tert-Butoxycarbonyl-4-piperidinemethanol

A solution of 1-tert-butoxycarbonyl isonipecotic acid (40 g, 0.17 mol)and N-methylmorpholine (19 mL, 0.17 mol) in tetrahydrofuran (900 mL) at−10° C. was treated with ethyl chloroformate (17 mL, 0.17 mol). After0.5 h, sodium borohydride was added (19.8 g, 0.5 mol) in one portionfollowed by slow addition of methanol. After gas evolution ceased, themixture was concentrated and the residue was diluted with 10% aqueousacetic acid and partitioned between ethyl acetate and water. The aqueouslayer was washed with EtOAc (2×) and the combined organic extracts weredried with magnesium sulfate, filtered, and concentrated to a solidresidue which was purified by column chromatography (SiO₂: 10 to 50%EtOAc:hexanes) providing the title compound (33.8 g, 90%) as a whitesolid.

¹H-NMR;

B. 1-tert-Butoxycarbonyl-4-piperidinecarboxaldehyde

A solution of oxalyl chloride (6 mL, 70 mmol) in dichloromethane (60 mL)at −78° C. was treated dropwise with dimethyl sulfoxide (10 mL, 0.14mol). After 15 minutes, 1-tert-butoxycarbonyl-4-piperidinemethanol (3.0g, 14 mmol) was added as a solution in dichloromethane (35 mL). Themixture was stirred at −78° C. for 1 hr, then triethylamine (29 mL, 0.21mol) was added dropwise. The mixture was warmed to ambient temperatureand poured into a saturated ammonium chloride solution (200 mL). Theorganic layer was separated and the aqueous layer was washed withdichloromethane (75 mL). The organic layers were combined and washedwith brine (75 mL); then dried with MgSO₄, filtered and concentrated.The residue was redissolved in ethyl acetate-hexanes (1:1) and filteredthrough Florisil (100-200 mesh). The resulting filtrate was concentratedyielding 3.0 g (100%) of the title aldehyde as a yellow oil; which wasused without further purification.

¹H-NMR.

C.N-(5-Chloropyridin-2-yl)-2-(1-Boc-piperidin-4-yl-methylidene)aminobenzamide

A solution containing 1-tert-butoxycarbonyl-4-piperidinecarboxaldehyde(500 mg, 2.34 mmol), 2-amino-N-(5-chloropyridin-2-yl)benzamide (580 mg,0.23 mmol), and pyridinium p-toluenesulfonate (58 mg, 0.23 mmol) inbenzene (250 mL) was heated at reflux with azeotropic removal of water.After 16 h, the mixture was concentrated and the residue partitionedbetween EtOAc (300 mL) and water (150 mL). The organic phase wasseparated and washed again with water (150 mL), brine (150 mL); thendried with MgSO₄, filtered and concentrated to afford, afterpurification by column chromatography (SiO₂: 0 to 10% EtOAc:methylenechloride), 750 mg (72%) of the title compound.

¹H-NMR; IS-MS, m/e (m).

D. N-(5-Chloropyridin-2-yl)-2-(piperidin-4-ylmethylamino)benzamide

A solution containingN-(5-chloropyridin-2-yl)-2-(1-Boc-piperidin-4-yl-methylidene)aminobenzamide(1.35 g, 3.05 mmol) and borane trimethylamine complex (667 mg, 9.14mmol) in glacial acetic acid (50 mL) was heated at reflux for 2 h. Themixture was concentrated and the residue was dissolved in methanol and12 N HCl. After 24 h, the mixture was concentrated, the residue wasdissolved in 2 N ammonia in methanol and concentrated. The residue wastriturated from methanol:EtOAc yielding 1.03 g (98%) of the titlecompound.

¹H-NMR; IS-MS, m/e (m).

EXAMPLE 48 Preparation ofN-(5-Chloropyridin-2-yl)-2-(1-isopropylpiperidin-4-ylmethylamino)benzamide

A solution ofN-(5-chloropyridin-2-yl)-2-(piperidin-4-ylmethylamino)benzamide (0.152g, 0.4 mmol) in methanol-acetic acid (95:5) (5 mL) was treated withacetone (5 mL) and sodium cyanoborohydride (0.111 g, 1.8 mmol). Thereaction mixture was stirred at room temperature for 24 h, then it wasdiluted with 1 N NaOH until pH 13 and extracted with dichloromethane.The organic extracts were combined, dried with MgSO₄, filtered andconcentrated in vacuo to provide the title compound (0.158 g, 92%). Thecrude material was triturated in dichloromethane-hexanes, giving a whitepowder which was filtered and dried under vacuum at 60° C.

¹H-NMR; mp 277.4-280.0° C.; FD-MS, m/e 387.0 (m); Analysis forC₂₁H₂₇N₄OCl.1CH₂Cl₂.0.68CH₃OH: Calcd: C, 55.18; H, 6.48; N, 11.35;Found: C, 54.78; H, 6.19; N, 11.77.

EXAMPLE 49 Preparation ofN-(5-Chloropyridin-2-yl)-2-[(1-methylsulfonylpiperidin-4-ylcarbonyl)amino]benzamide

A. Ethyl N-Methylsulfonylisonipecotate

A solution of ethyl isonipecotate (4.9 mL, 31.8 mmol) and pyridine (2.8mL, 34.6 mmol) was cooled to 0° C. Methanesulfonyl chloride (2.7 mL,34.9 mmol) was added. After 1.5 hours, the reaction mixture was dilutedwith CH₂Cl₂ (300 mL) and extracted with saturated aqueous NaHCO₃ (3×100mL). The organic layer was dried over Na₂SO₄, filtered, andconcentrated. The crude material was dissolved in EtOAc (400 mL),extracted with H₂O (3×50 mL), dried over Na₂SO₄, filtered, andconcentrated to give the pure product (5.42 g, 22.9 mmol, 72%) as ayellow solid.

IR (CHCl₃): 3027, 1726, 1331, 1158, 963. ¹H-NMR (400 MHz, DMSO-d₆): δ8.08 (q, J=7.2 Hz, 2H); 3.44 (d, J=11.6 Hz, 2H); 2.81 (s, 3H); 2.76 (t,J=8.7 Hz, 2H); 2.47 (m, 1H); 1.89 (d, J=13.2 Hz, 2H); 1.56 (m, 2H); 1.15(t, J=7.2 Hz, 3H). IS-MS, m/e: 236.0 (m+1). Analysis forC₉H₁₇NO₄S.0.25H₂O: Calcd: C, 45.08; H, 7.36; N, 5.84; Found: C, 45.31;H, 7.08; N, 5.88.

B. N-Methylsulfonylisonipecotic Acid

Using a procedure similar to example 46-B, N-methylsulfonylisonipecoticacid (1.6 g, 34%) was prepared from ethyl N-methylsulfonylisonipecotate

IR (CHCl₃): 1710, 1346, 1331, 1158, 961. ¹H-NMR (300 MHz, DMSO-d₆): δ3.42 (d, J=11.7 Hz, 2H); 2.81 (s, 3H); 2.75 (m, 2H); 2.33 (m, 1H); 1.87(d, J=13.8 Hz, 2H); 1.52 (m, 2H). MS-FIA m/e: 208.0 (m+1). Analysis forC₇H₁₃NO₄S: Calcd: C, 40.57; H, 6.32; N, 6.76; Found: C, 40.68; H, 6.24;N, 6.70.

C.N-(5-Chloropyridin-2-yl)-2-[(1-methylsulfonylpiperidin-4-ylcarbonyl)amino]benzamide

Using a procedure similar to that used in example 34-A,N-(5-chloropyridin-2-yl)-2-[(1-methylsulfonylpiperidin-4-ylcarbonyl)amino]benzamide(751 mg, 78%) was prepared from2-amino-N-(5-chloropyridin-2-yl)benzamide andN-methylsulfonylisonipecotic acid.

IR (CHCl₃): 1663, 1588, 1506, 1375. ¹H-NMR (400 MHz, DMSO-d₆): d 10.95(s, 1H); 10.34 (s, 1H); 8.40 (s, 1H); 8.12 (d, J=8.0 Hz, 1H); 7.94 (d,J=8.4 Hz, 2H); 7.73 (d, J=8.0 Hz, 1H); 7.49 (t, J=8.0 Hz, 1H); 7.17 (d,J=8.0 Hz, 1H); 3.51 (d, J=11.6 Hz, 2H); 2.82 (s, 3H); 2.73 (t, J=11.6Hz, 2H); 2.47 (m, 1H); 1.87 (d, J=10.0 Hz, 2H). MS-FIA m/e: 437.2 (n+1).

EXAMPLE 50 Preparation of5-Chloro-2-[(1-isopropyl-3,4-didehydropiperidin-4-ylcarbonyl)amino]-N-(5-methylpyridin-2-yl)benzamideHydrochloride

A. 5-Chloro-N-(5-methylpyridin-2-yl)-2-nitrobenzamide

Using methods substantially equivalent to those described in example34-A, 5-chloro-N-(5-methylpyridin-2-yl)-2-nitrobenzamide (11.4 g, 53%)was prepared from 2-amino-5-methylpyridine and 5-chloro-2-nitrobenzoicacid.

¹H-NMR; IS-MS, m/e 292.0 (m+1); Analysis for C₁₃H₁₀N₃O₃Cl: Calcd: C,53.53; H, 3.46; N, 14.40; Found: C, 53.76; H, 3.41; N, 14.35.

B. 2-Amino-5-chloro-N-(5-methylpyridin-2-yl)benzamide

Using methods substantially equivalent to those described in example2-B, 2-amino-5-chloro-N-(5-methylpyridin-2-yl)benzamide (2.4 g, 67%) wasprepared from 5-chloro-N-(5-methylpyridin-2-yl)-2-nitrobenzamide

¹H-NMR; IS-MS, m/e 262.0 (m+1); Analysis for C₁₃H₁₂N₃OCl: Calcd: C,59.66; H, 4.62; N, 16.06; Found: C, 59.89; H, 4.57; N, 15.99.

C.2-[(1-boc-3,4-Didehydropiperidin-4-ylcarbonyl)amino]-5-chloro-N-(5-methylpyridin-2-yl)benzamide

Using methods substantially equivalent to those described in example25-D,2-[(1-Boc-3,4-didehydropiperidin-4-ylcarbonyl)amino]-5-chloro-N-(5-methylpyridin-2-yl)benzamide(0.37 g, 39%) was prepared from2-amino-5-chloro-N-(5-methylpyridin-2-yl)benzamide and1-Boc-1,2,3,6-tetrahydro-4-pyridinecarboxylic acid.

¹H-NMR; IS-MS, m/e 471.3 (m+1).

D.5-Chloro-2-[(3,4-didehydropiperidin-4-ylcarbonyl)amino]-N-(5-methylpyridin-2-yl)benzamideTrifluoroacetate

Using methods substantially equivalent to those described in example9-B,5-chloro-2-[(3,4-didehydropiperidin-4-ylcarbonyl)amino]-N-(5-methylpyridin-2-yl)benzamidetrifluoroacetate (0.305 g, 95%) was prepared from2-[(1-Boc-3,4-didehydropiperidin-4-ylcarbonyl)amino]-5-chloro-N-(5-methylpyridin-2-yl)benzamide

¹H-NMR; IS-MS, m/e 371.1 (m+1).

E.5-Chloro-2-[(1-isopropyl-3,4-didehydropiperidin-4-ylcarbonyl)amino]-N-(5-methylpyridin-2-yl)benzamideHydrochloride

Using methods substantially equivalent to those described in example 27,5-chloro-2-[(1-isopropyl-3,4-didehydropiperidin-4-ylcarbonyl)amino]-N-(5-methylpyridin-2-yl)benzamidehydrochloride (90 mg, 3.5%) was prepared from5-chloro-2-[(3,4-didehydropiperidin-4-ylcarbonyl)amino]-N-(5-methylpyridin-2-yl)benzamidetrifluoroacetate The preparative RPHPLC (C18) purification procedure waselution with a linear gradient of 90/10 to 50/50 (0.01%HCl/acetonitrile) over 180 min.

¹H-NMR; IS-MS, m/e 413.2 (m+1); Analysis for C₂₂H₂₅N₄O₂Cl.1.4HCl.0.2H₂O:Calcd: C, 56.51; H, 5.78; N, 11.98; Cl, 18.20; Found: C, 56.55; H, 5.69;N, 11.84; Cl, 18.06.

EXAMPLE 51 Preparation of5-Chloro-N-(5-chloropyridin-2-yl)-2-[(4-isopropylpiperazin-1-ylcarbonyl)aminol]benzamideHydrochloride

A. 2-[(4-boc-Piperazin-1-ylcarbonyl)amino]-5-chlorobromobenzene

To a stirring solution of triphosgene (2.7 g, 9.0 mmol) indichloromethane (100 mL) was added, dropwise via an addition funnel, asolution of 2-bromo-4-chloroaniline (5 g, 24.2 mmol) andN,N-diisopropylethylamine (6.9 g, 53.2 mmol) in dichloromethane (50 mL).After complete addition and an additional hour, a solution ofN-Boc-piperazine (5 g, 26.6 mmol) in dichloromethane (50 mL) was added.After stirring overnight, the solvent was removed in vacuo and theresidue was partitioned between ethyl acetate and water. The organicphase was separated and washed consecutively with 1 M citric acid,brine, sat. aq sodium bicarbonate and finally with brine, then driedwith MgSO4, filtered and concentrated in vacuo. The residue was thendissolved in a minimal amount of chloroform and chromatographed oversilica gel, eluting with 20% ethyl acetate in hexanes followed by 30%ethyl acetate in hexanes. The product containing fractions were combinedand concentrated in vacuo and the resulting solid was suspended indiethyl ether, sonicated and then filtered and dried in vacuo to give7.2 g (71%) of a white powder.

¹H-NMR; IS-MS, m/e 418.2 ((m−1)⁻.

B. 2-[(4-boc-Piperazin-1-ylcarbonyl)amino]-5-chlorobenzoic Acid

To a stirred solution of2-[(4-Boc-piperazin-1-ylcarbonyl)amino]-5-chlorobromobenzene (0.7 g,1.67 mmol) in tetrahydrofuran (10 mL) at −78° C. under nitrogen wasadded methyllithium (1.4 M in ether, 1.2 mL, 1.67 mmol) dropwise via asyringe. After 5 min, tert-butyllithium (1.7 M in pentane, 1.0 mL, 1.67mmol) was added dropwise via an addition funnel. After another 5 min,carbon dioxide was bubbled through the solution over 30 min as it warmedto room temperature. The solvent was then removed in vacuo and theresidue was partitioned between diethyl ether and water. The layers wereseparated and the aqueous phase was acidified to pH 4 with citric acidand then extracted with ethyl acetate. The organic phase was washed withsaturated aqueous sodium chloride, dried (magnesium sulfate), filtered,and concentrated in vacuo to give 0.32 g (50%) of the title compound asa white solid.

¹H-NMR; IS-MS, m/e 382.3 (m−1)⁻; Analysis for C₁₇H₂₂N₃O₅Cl: Calcd: C,53.20; H, 5.78; N, 10.95; Found: C, 52.97; H, 5.53; N, 10.74.

C. 2-(4-boc-1-Piperazinyl)-6-chloro-4H-3,1-benzoxazin-4-one

To a stirring solution of2-[(4-Boc-piperazin-1-ylcarbonyl)amino]-5-chlorobenzoic acid (1.6 g,4.17 mmol) in DMF (30 mL) was added1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (2.4 g,12.51 mmol). After 30 min, the solvent was removed in vacuo and theresidue was partitioned between ethyl acetate and water. The layers wereseparated and the organic phase was washed consecutively with 1 M citricacid, brine, sat. aq sodium bicarbonate, and brine, then dried withMgSO₄, filtered and concentrated in vacuo. The residue was thensuspended in diethyl ether, sonicated, filtered and dried in vacuo togive 0.86 g (58%) of the title compound as a white solid.

¹H-NMR; IS-MS, m/e 366.1 (m+1).

D.2-[(4-boc-Piperazin-1-ylcarbonyl)amino]-5-chloro-N-(5-chloropyridin-2-yl)benzamide

To a stirred solution of 2-amino-5-chloropyridine (0.6 g, 4.64 mmol) intetrahydrofuran (80 mL) at 0° C. under nitrogen was added allylmagnesiumbromide (1.0 M in ether, 4.7 mL, 4.7 mmol) dropwise via a syringe. Afterstirring at 0° C. for 10 min,2-(4-Boc-1-piperazinyl)-6-chloro-4H-3,1-benzoxazin-4-one (0.8 g, 2.19mmol) was added. After stirring 15 h at room temperature, the solventwas removed in vacuo. The residue was partitioned between ethyl acetateand saturated aqueous sodium chloride and the layers separated. Theorganic phase was washed with water, dried (magnesium sulfate),filtered, and concentrated in vacuo to give 0.88 g (82%) of the titlecompound as a white solid.

¹H-NMR; IS-MS, m/e 494.1 (m+1).

E.5-Chloro-N-(5-chloropyridin-2-yl)-2-[(piperazin-1-ylcarbonyl)amino]benzamideTrifluoroacetate

Using methods substantially equivalent to those described in example9-B,N-(5-chloropyridin-2-yl)-2-[(piperazin-4-ylcarbonyl)amino]-5-chlorobenzamidetrifluoroacetate (0.607 g, 98%) was prepared from2-[(4-Boc-piperazin-1-ylcarbonyl)amino]-5-chloro-N-(5-chloropyridin-2-yl)benzamide

¹H-NMR; IS-MS, m/e 394.1 (m+1); Analysis for C₁₇H₁₇N₅O₂Cl₂.TFA: Calcd:C, 44.90; H, 3.57; N, 13.78; F, 11.21; Found: C, 44.60; H, 3.53; N,13.78; F, 11.43.

F.5-Chloro-N-(5-chloropyridin-2-yl)-2-[(4-isopropylpiperazin-1-ylcarbonyl)amino]benzamideHydrochloride

Using methods substantially equivalent to those described in example 27,5-chloro-N-(5-chloropyridin-2-yl)-2-[(4-isopropylpiperazin-1-ylcarbonyl)amino]benzamidehydrochloride (0.263 g, 57%) was prepared from5-chloro-N-(5-chloropyridin-2-yl)-2-[(piperazin-1-ylcarbonyl)amino]-benzamidetrifluoroacetate

¹H-NMR; IS-MS, m/e 436.1 (m+1); Analysis forC₂₀H₂₃N₅O₂Cl₂.2.0HCl.0.1H₂O: Calcd: C, 47.00; H, 4.97; N, 13.70; Cl,27.75; Found: C, 47.07; H, 4.70; N, 13.57; Cl, 27.74.

EXAMPLE 52 Preparation ofN-(5-Chloropyridin-2-yl)-2-[1-(4-pyridinyl)piperidin-4-ylmethylamino]benzamide

A pressure tube was charged withN-(5-chloropyridin-2-yl)-2-(piperidin-4-ylmethylamino)benzamide (100 mg,0.29 mmol), 4-chloropyridine hydrochloride (87 mg, 0.58 mmol),triethylamine (59 mg, 0.58 mmol), and ethanol (5 mL), sealed, and placedin a 120° C. bath. After 24 h, the mixture was cooled, concentrated, andthe residue purified by column chromatography (SiO₂: 5 to 10% 2 Nammonia in methanol:methylene chloride) affording 70 mg (57%) of thetitle compound.

¹H-NMR, IR; IS-MS, m/e 422 (m); Analysis for C₂₃H₂₄ClN₅O0.25H₂O: Calcd:C, 64.78; H, 5.79; N, 16.42; Found: C, 64.54; H, 6.25; N, 15.58.

EXAMPLE 53 Preparation of5-Chloro-N-(5-chloropyridin-2-yl)-2-[[1-(1-ethylpropyl)piperidin-4-ylcarbonyl]amino]benzamideHydrochloride

By methods substantially equivalent to those described in Example 27,5-chloro-N-(5-chloropyridin-2-yl)-2-[[1-(1-ethylpropyl)piperidin-4-ylcarbonyl]amino]benzamidehydrochloride (0.103 g, 21%) was prepared from5-chloro-N-(5-chloropyridin-2-yl)-2-[(piperidin-4-ylcarbonyl)amino]-benzamidetrifluoroacetate and 3-pentanone. The product was purified with reversephase HPLC, eluting with a gradient from 20% through 60% acetonitrile in0.05% aq HCl.

¹H-NMR; IS-MS, m/e 463.3 (m+1); Analysis for C₂₃H₂₈N₄O₂Cl₂.1.2HCl.H₂O:Calcd: C, 52.60; H, 5.99; N, 10.67; Cl, 21.60; Found: C, 52.53; H, 6.08;N, 10.41; Cl, 21.51.

EXAMPLE 54 Preparation ofN-(5-Chloropyridin-2-yl)-2-[(1-isopropylazetidin-3-yloxycarbonyl)amino]benzamide

A.N-(5-Chloropyridin-2-yl)-2-[(1-tert-butoxycarbonylazetidin-3-yloxycarbonyl)amino]benzamide

Using a similar procedure to that described in example 4-B,2-amino-N-(5-chloropyridin-2-yl)benzamide (1.07 g, 4.34 mmol) and1-tert-butoxycarbonyl-3-hydroxyazetidine (1.50 g, 8.67 mmol) yielded1.43 g (74%) of the title compound.

¹H-NMR; IS-MS, m/e 447 (m+1).

B.N-(5-Chloropyridin-2-yl)-2-[(1-isopropylazetidin-3-yl-oxycarbonyl)amino]benzamide

Using a similar procedure to that described for Example 9-B&C,N-(5-chloropyridin-2-yl)-2-[(1-tert-butoxycarbonylazetidin-3-yloxycarbonyl)amino]benzamide(327 mg, 0.733 mmol) afforded 201 mg (71%) of the title compound.

¹H-NMR; IS-MS, m/e 389 (m).

EXAMPLE 55 Preparation ofN-(5-Chloropyridin-2-yl)-2-[(1-isopropylpyrrolidin-3-yloxycarbonyl)amino]benzamide

A.N-(5-Chloropyridin-2-yl)-2-[(1-tert-butoxycarbonylpyrrolidin-3-yloxycarbonyl)amino]benzamide

Using a similar procedure to that described in Example 4-B,N-(5-chloropyridin-2-yl)-2-aminobenzamide (1.25 g, 5.05 mmol) and1-tert-butoxycarbonyl-3-hydroxypyrrolidine yielded 2.33 g (99%) of thetitle compound.

¹H-NMR; IS-MS, m/e 461 (m).

B.N-(5-Chloropyridin-2-yl)-2-[(pyrrolidin-3-yloxycarbonyl)amino]benzamideTrifluoroacetate

Using a similar procedure to that described in Example 9-B,N-(5-chloropyridin-2-yl)-2-[(-tert-butoxycarbonylpyrrolidin-3-yloxycarbonyl)amino]benzamide(1.50 g, 3.26 mmol) yielded 1.60 g (94%) of the title compound.

¹H-NMR.

C.N-(5-Chloropyridin-2-yl)-2-[(1-isopropylpyrrolidin-3-yloxycarbonyl)amino]benzamide

Using a similar procedure to that described in Example 9-C,N-(5-chloropyridin-2-yl)-2-[pyrrolidin-3-yloxycarbonyl)amino]benzamidetrifluoroacetate (500 mg, 1.06 mmol), acetone (10 mL), and sodiumcyanoborohydride (265 mg, 4.22 mmol) yielded 330 mg (77%) of the titlecompound.

¹H-NMR; IS-MS, m/e 403 (m+1).

EXAMPLE 56 Preparation ofN-(5-Chloropyridin-2-yl)-2-[(1-cyclohexylpyrrolidin-3-yloxycarbonyl)amino]benzamide

Using a similar procedure to that described in Example 9-C,N-(5-chloropyridin-2-yl)-2-[(pyrolidin-3-yloxycarbonyl)amino]benzamidetrifluoroacetate (100 mg, 0.211 mmol), cyclohexanone (0.11 mL, 1.05mmol), and sodium cyanoborohydride (53 mg, 0.84 mmol) yielded 90 mg(96%) of the title compound.

¹H-NMR; IS-MS, m/e 443 (m+1).

EXAMPLE 57 Preparation ofN-(5-Chloropyridin-2-yl)-2-[(1-cyclopentylpyrrolidin-3-yloxycarbonyl)amino]benzamide

Using a similar procedure to that described in Example 9-C,N-(5-chloropyridin-2-yl)-2-[(pyrrolidin-3-yloxycarbonyl)amino]benzamidetrifluoroacetate (100 mg, 0.211 mmol), cyclopentanone (0.095 mL, 1.05mmol), and sodium cyanoborohydride (53 mg, 0.84 mmol) yielded 78 mg(87%) of the title compound.

¹H-NMR; IS-MS, m/e 429 (m+1).

EXAMPLE 58 Preparation ofN-(5-Chloropyridin-2-yl)-2-[1-(2-cyanopyridin-4-yl)piperidin-4-ylmethylamino]benzamide

Using a similar procedure to that described in Example 52,N-(5-chloropyridin-2-yl)-2-(piperidin-4-ylmethylamino)benzamide (100 mg,0.29 mmol), 4-chloro-2-cyanopyridine (80 mg, 0.58 mmol), triethylamine(59 mg, 0.58 mmol), and ethanol (2 mL) yielded 60 mg (46%) of the titlecompound.

¹H-NMR, IR; IS-MS, m/e 447 (m+1); Analysis for C₂₄H₂₃ClN₆O0.1OH₂O:Calcd: C, 62.00; H, 5.42; N, 18.07; Found: C, 62.14; H, 5.27; N, 17.33.

EXAMPLE 59 Preparation ofN-(5-Chloropyridin-2-yl)-5-fluoro-2-(piperidin-4-ylmethylamino)benzamide

A.2-(1-boc-Piperidin-4-ylmethylidene)amino-N-(5-chloropyridin-2-yl)-5-fluorobenzamide

A solution containing 1-Boc-piperidine-4-carboxaldehyde (3.0 g, ca. 14mmol), 2-amino-N-(5-chloropyridin-2-yl)-5-fluorobenzamide (3.7 g, 14mmol), and pyridinium p-toluenesulfonate (0.3 g, 1.4 mmol) in benzene(250 mL) was heated at reflux for 24 h with azeotropic removal of water.The solution was allowed to cool to room temperature; then the solventwas removed in vacuo and the residue was partitioned between ethylacetate (300 mL) and water (150 mL). The organic phase was separated andwashed again with water (150 mL) and then brine (150 mL); then driedwith MgSO₄, filtered and concentrated in vacuo to give 6.0 g (93%) ofthe title compound as an orange foam which was used directly in the nextstep without further purification.

¹H-NMR; FD-MS, m/e 461.1 (m).

B.2-(1-boc-Piperidin-4-ylmethylamino)-N-(5-chloropyridin-2-yl)-5-fluorobenzamide

A solution containing2-(1-Boc-piperidin-4-yl-methylidene)amino-N-(5-chloropyridin-2-yl)-5-fluorobenzamidefrom above (6.0 g, 13 mmol) and borane trimethylamine complex (2.9 g, 39mmol) in glacial acetic acid (100 mL) was heated at 70°0 C. for 24 h.The solution was allowed to cool to room temperature; then the solventwas removed in vacuo, and the residue was partitioned betweendichloromethane (200 mL) and water (100 mL). The biphasic mixture wastreated with 2 N NaOH until neutral; then the organic layer wasseparated and the aqueous layer was washed again with dichloromethane(100 mL). The combined organic layers were washed with brine (100 mL),dried with MgSO₄, and filtered. The filtrate was concentrated in vacuoto give 5.85 g (97%) of the title compound as an orange foam which wasused directly in the next step without further purification.

¹H-NMR; FD-MS, m/e 463.1 (m).

C.N-(5-Chloropyridin-2-yl)-5-fluoro-2-(piperidin-4-ylmethylamino)benzamide

A solution of2-(1-Boc-piperidin-4-ylmethylamino)-N-(5-chloropyridin-2-yl)-5-fluorobenzamidefrom above (5.8 g, 12 mmol) in trifluoroacetic acid (125 mL) was heatedat 70° C. for 2 h, then at room temperature for 24 h. The solvent wasremoved in vacuo; then the residue was directly applied to a silica gelcolumn. Elution with dichloromethane-2 M ammonia in methanol (9:1)afforded 3.8 g (84%) of the title compound as a yellow solid.

¹H-NMR; mp 230-233° C; FD-MS, m/e 363.3 (m); Analysis forC₁₈H₂₀ClFN₄O.1.28CH₂Cl₂: Calcd: C, 49.11; H, 4.82; N, 11.88; Found: C,49.30; H, 4.49; N, 11.49.

EXAMPLE 60 Preparation of5-Chloro-N-(5-chloropyridin-2-yl)-2-(piperidin-4-ylmethylamino)benzamide

A.2-(1-boc-piperidin-4-ylmethylamino)-5-chloro-N-(5-chloropyridin-2-yl)benzamide

To a solution of 1-Boc-piperidine-4-carboxaldehyde (3.5 g, 14 mmol) and2-amino-5-chloro-N-(5-chloropyridin-2-yl)benzamide (3.9 g, 14 mmol) inbenzene (250 mL), a catalytic amount of pyridinium p-toluenesulfonate(0.35 g, 1.4 mmol) was added, followed by 4A molecular sieves. Thereaction mixture was heated at reflux for 48 h with azeotropic removalof water. The mixture was subsequently filtered through a pad ofdiatomaceous earth, washing well with ethyl acetate. The filtrate wasconcentrated in vacuo to a residue that was taken up in acetic acid (100mL) and treated with borane-trimethylamine complex (3 g, 42 mmol). Themixture was heated at 70° C. for 24 h; then it was diluted with 2 N NaOHand extracted with dichloromethane The water layer was neutralized withsolid sodium bicarbonate, and further extracted with dichloromethane Thecombined organic extracts were dried with MgSO₄, filtered, andconcentrated in vacuo to a solid residue (8 g, >100%) which wasidentified as the desired product and taken on directly to the next stepwithout further purification.

¹H-NMR; FD-MS, m/e 479.0 (m).

B.5-Chloro-N-(5-chloropyridin-2-yl)-2-(piperidin-4-yl-methylamino)benzamide

Using the procedure described in example 47-D,2-(1-Boc-piperidin-4-ylmethylamino)-5-chloro-N-(5-chloropyridin-2-yl)benzamide(8 g, 14 mmol) was converted to5-chloro-N-(5-chloropyridin-2-yl)-2-(piperidin-4-ylmethylamino)benzamide,which was purified via silica gel chromatography. Elution with 9:1dichloromethane-2 N ammonia in methanol provided clean materialidentified as the title compound (3.8 g, 72%).

¹H-NMR; mp 91.4-93.4° C.; FD-MS, m/e 379.1 (m); Analysis forC₁₈H₂₀N₄OCl₂.0.2MeOH: Calcd: C, 56.68; H, 5.44; N, 14.53; Found: C,56.45; H, 5.13; N, 14.32.

EXAMPLE 61 Preparation of5-Chloro-N-(5-fluoropyridin-2-yl)-2-[[1-(4-pyridinyl)piperidin-4-ylcarbonyl]amino]benzamideHydrochloride

A. 5-Chloro-N-(5-fluoropyridin-2-yl)-2-nitrobenzamide

Using methods substantially equivalent to those described in example34-A, 5-chloro-N-(5-fluoropyridin-2-yl)-2-nitrobenzamide (4.27 g, 81%)was prepared from 2-amino-5-fluoropyridine and 5-chloro-2-nitrobenzoicacid.

¹H-NMR; IS-MS, m/e 296.2 (m+1); Analysis for C₁₂H₇N₃O₃ClF: Calcd: C,48.75; H, 2.39; N, 14.21; Found: C, 48.97; H, 2.61; N, 14.13.

B. 2-Amino-5-chloro-N-(5-fluoropyridin-2-yl)benzamide

Using methods substantially equivalent to those described in example2-B, 2-amino-5-chloro-N-(5-fluoropyridin-2-yl)benzamide (1.87 g, 88%)was prepared from 5-chloro-N-(5-fluoropyridin-2-yl)-2-nitrobenzamide

¹H-NMR; IS-MS, m/e 266.0 (m+1).

C.5-Chloro-N-(5-fluoropyridin-2-yl)-2-[[1-(4-pyridinyl)piperidin-4-ylcarbonyl]amino]benzamideHydrochloride

Using methods substantially equivalent to those described in example1-D,5-chloro-N-(5-fluoropyridin-2-yl)-2-[[1-(4-pyridinyl)piperidin-4-ylcarbonyl]amino]benzamidehydrochloride (0.365 g, 40%) was prepared from2-amino-5-chloro-N-(5-fluoropyridin-2-yl)benzamide and1-(4-pyridinyl)piperidin-4-ylcarbonyl chloride. The preparative RPHPLC(C18) purification procedure was elution with a linear gradient of 90/10to 50/50 (0.01% HCl/acetonitrile) over 180 min.

¹H-NMR; IS-MS, m/e 455.2 (m+1); Analysis forC₂₃H₂₁N₅O₂ClF.1.1HCl.1.5H₂O: Calcd: C, 53.02; H, 4.86; N, 13.44; Cl,14.29; Found: C, 53.16; H, 4.47; N, 13.29; Cl, 14.25.

EXAMPLE 62 Preparation ofN-(5-Chloropyridin-2-yl)-5-fluoro-2-(1-isopropylpiperidin-4-ylmethylamino)benzamide

Using the procedure described in example 48,N-(5-chloropyridin-2-yl)-5-fluoro-2-(piperidin-4-ylmethylamino)benzamide(0.7 g, 1.9 mmol) was converted toN-(5-chloropyridin-2-yl)-5-fluoro-2-(1-isopropylpiperidin-4-ylmethylamino)benzamide,which was purified via silica gel chromatography. Elution withdichloromethane-2 M ammonia in methanol (9:1) afforded 0.6 g (83%) ofthe title compound as a yellow solid.

¹H-NMR; mp 142-144° C.; FD-MS, m/e 405.4 (m); Analysis for C₂₁H₂₆ClFN₄O:Calcd: C, 62.29; H, 6.47; N, 13.84; Found: C, 62.03; H, 6.58; N, 13.83.

EXAMPLE 63 Preparation of5-Chloro-N-(5-chloropyridin-2-yl)-2-(1-isopropylpiperidin-4-ylmethylamino)benzamide

Using the procedure described in example 48,5-chloro-N-(5-chloropyridin-2-yl)-2-(piperidin-4-ylmethylamino)benzamide(0.626 g, 1.7 mmol) was converted to5-chloro-N-(5-chloropyridin-2-yl)-2-(1-isopropylpiperidin-4-ylmethylamino)benzamide.The crude reaction mixture was filtered through a pad of diatomaceousearth and concentrated in vacuo. The residue was diluted with methanoland applied to an SCX column, washed with methanol and eluted with 2 Nammonia in methanol. The eluted fractions were combined and concentratedin vacuo to provide a crude residue, which was further purified viasilica gel chromatography. Elution with ethyl acetate, then ethylacetate-2 N ammonia in methanol (95:5), then dichloromethane-2 N ammoniain methanol (90:10) provided the title compound (0.375 g, 54%) as asolid material.

¹H-NMR; FD-MS, m/e 421.0 (m); Analysis for C₂₁H₂₆N₄OCl₂.0.4CH₃OH: Calcd:C, 59.20; H, 6.41; N, 12.90; Found: C, 58.91; H, 6.12; N, 12.75.

EXAMPLE 64 Preparation ofN-(5-Chloropyridin-2-yl)-2-[[1-(2-methylcyclopentyl)pyrrolidin-3-yloxycarbonyl)amino]benzamideHydrochloride

Using a similar procedure to that described in Example 9-C,N-(5-chloropyridin-2-yl)-2-[(pyrrolidin-3-yloxycarbonyl)amino]benzamidetrifluoroacetate (100 mg, 0.211 mmol), 2-methylcyclopentanone (0.112 mL,1.05 mmol), and sodium cyanoborohydride (53 mg, 0.84 mmol) yielded,after treatment with HCl, 80 mg (80%) of the title compound as thehydrochloride salt.

¹H-NMR; IS-MS, m/e 443 (m+1).

EXAMPLE 65 Preparation ofN-(5-Chloropyridin-2-yl)-2-[[1-(2-methylcyclohexyl)pyrrolidin-3-yloxycarbonyl]amino]benzamideHydrochloride

Using a similar procedure to that described in Example 9-C,N-(5-chloropyridin-2-yl)-2-[(pyrrolidin-3-yloxycarbonyl)amino]benzamidetrifluoroacetate (100 mg, 0.211 mmol), 2-methylcyclohexanone (0.12 mL,1.05 mmol), and sodium cyanoborohydride (53 mg, 0.84 mmol) yielded,after treatment with HCl, 82 mg (80%) of the title compound as thehydrochloride salt.

¹H-NMR; IS-MS, m/e 443 (m+1).

EXAMPLE 66 Preparation of2-[1-(3-Carboxypyridin-4-yl)piperidin-4-ylmethylamino]-N-(5-chloropyridin-2-yl)benzamide

Using a similar procedure to that described in Example 52,N-(5-chloropyridin-2-yl)-2-(piperidin-4-ylmethylamino)benzamide (100 mg,0.29 mmol), 4-chloronicotinic acid (91 mg, 0.58 mmol), triethylamine (59mg, 0.58 mmol), and ethanol (5 mL) yielded, after RPHPLC purification,45 mg (33%) of the title compound as a trifluoroacetate salt.

¹H-NMR, IR; IS-MS, m/e 466 (m+1); Analysis for C₂₄H₂₄ClN₅O₃(1.5H₂O,1.0CF₃CO₂H): Calcd: C, 51.44; H, 4.65; N, 11.54; Found: C, 51.46; H,4.76; N, 12.02.

EXAMPLE 67 Preparation ofN-(5-Chloropyridin-2-yl)-2-[(piperidin-4-ylmethoxycarbonyl)amino]benzamideTrifluoroacetic Acid Salt

A.N-(5-Chloropyridin-2-yl)-2-[(1-tert-butoxycarbonylpiperidin-4-ylmethoxycarbonyl)amino]benzamide

Using a similar procedure to that described in Example 4-B,2-amino-N-(5-chloropyridin-2-yl)benzamide (1.50 g, 6.07 mmol) and1-tert-butoxycarbonyl-4-hydroxymethylpiperidine (1.96 g, 9.10 mmol)yielded 2.00 g (67%) of the title compound.

¹H-NMR; IS-MS, m/e 489 (m+1); Analysis for C₂₄H₂₉N₄O₅Cl: Calcd: C,58.95; H, 5.98; N, 11.46; Found: C, 59.23; H, 6.09; N, 11.70.

B.N-(5-Chloropyridin-2-yl)-2-[(piperidin-4-ylmethoxycarbonyl)amino]benzamideTrifluoroacetic Acid Salt

Using a similar procedure to that described in Example 9-B,N-(5-chloropyridin-2-yl)-2-[(1-tert-butoxycarbonylpiperidin-4-ylmethoxycarbonyl)amino]benzamide(300 mg, 0.615 mmol) yielded 308 mg (99%) of the title compound as atrifluoroacetate salt.

¹H-NMR; IS-MS, m/e 389 (m+1); Analysis for C₂₁H₂₂N₄O₅ClF₃: Calcd: C,50.16; H, 4.41; N, 11.14; Found: C, 50.39; H, 4.40; N, 11.24.

EXAMPLE 68 Preparation ofN-(5-Chloropyridin-2-yl)-2-[(piperidin-4-yloxycarbonyl)amino]benzamideTrifluoroacetic Acid Salt

A.N-(5-Chloropyridin-2-yl)-2-[(1-tert-butoxycarbonylpiperidin-4-yloxycarbonyl)amino]benzamide

Using a similar procedure to that described in Example 4-B,2-amino-N-(5-chloropyridin-2-yl)benzamide (1.50 g, 6.07 mmol) and1-tert-butoxycarbonyl-4-hydroxypiperidine (1.83 g, 9.10 mmol) yielded2.20 g (76%) of the title compound.

¹H-NMR; IS-MS, m/e 475 (m+1).

B.N-(5-Chloropyridin-2-yl)-2-[(piperidin-4-yloxycarbonyl)amino]benzamideTrifluoroacetic Acid Salt

Using a similar procedure to that described in Example 9-B,N-(5-chloropyridin-2-yl)-2-[(1-tert-butoxycarbonylpiperidin-4-yloxycarbonyl)amino]benzamide(1.90 g, 4.00 mmol) yielded 1.95 g (99%) of the titled compound as atrifluoroacetate salt.

¹H-NMR; IS-MS, m/e 375 (m+1); Analysis for C₂₀H₂₀N₄O₅ClF₃: Calcd: C,49.14; H, 4.12; N, 11.46; Found: C, 49.21; H, 4.02; N, 11.57.

EXAMPLE 69 Preparation of5-Chloro-N-(5-chloropyridin-2-yl)-2-[[1-(tetrahydropyran-4-yl)piperidin-4-ylcarbonyl]amino]benzamideHydrochloride

Using methods substantially equivalent to those described in example 27,5-chloro-N-(5-chloropyridin-2-yl)-2-[1-(tetrahydropyran-4-yl)piperidin-4-ylcarbonyl]amino]-benzamidehydrochloride (0.25 g, 56%) was prepared from5-chloro-N-(5-chloropyridin-2-yl)-2-[(piperidin-4-ylcarbonyl)amino]benzamidetrifluoroacetate and tetrahydro-4H-pyran-4-one. The preparative RPHPLC(C18) purification procedure was elution with a linear gradient of 90/10to 50/50 (0.01% HCl/acetonitrile) over 180 min.

¹H-NMR; IS-MS, m/e 477.2 (m+1); Analysis forC₂₃H₂₆N₄O₃Cl₂.0.8HCl.0.7H₂O: Calcd: C, 53.21; H, 5.47; N, 10.79; Cl,19.12; Found: C, 53.24; H, 5.14; N, 10.96; Cl, 19.02.

EXAMPLE 70 Preparation of5-Chloro-N-(5-chloropyridin-2-yl)-2-[(1-cyclohexylpiperidin-4-ylcarbonyl)amino]benzamideHydrochloride

By methods substantially equivalent to those described in example 27,5-chloro-N-(5-chloropyridin-2-yl)-2-[(1-cyclohexylpiperidin-4-ylcarbonyl)amino]benzamidehydrochloride (0.127 g, 29%) was prepared from5-chloro-N-(5-chloropyridin-2-yl)-2-[(piperidin-4-ylcarbonyl)amino]-benzamidetrifluoroacetate and cyclohexanone. The preparative RPHPLC (C18)purification procedure was elution with a linear gradient of 90/10 to50/50 (0.01% HCl/acetonitrile) over 180 min.

¹H-NMR; IS-MS, m/e 475.1 (m+1); Analysis forC₂₄H₂₈N₄O₂Cl₂.1.2HCl.0.8H₂O: Calcd: C, 54.02; H, 5.82; N, 10.50; Cl,21.26; Found: C, 54.26; H, 5.56; N, 10.58; Cl, 21.22.

EXAMPLE 71 Preparation ofN-(5-Chloropyridin-2-yl)-2-[(1-isopropylpiperidin-4-yloxycarbonyl)amino]benzamideHydrochloride

Using a similar procedure to that described in Example 9-C,N-(5-chloropyridin-2-yl)-2-[(piperidin-4-yloxycarbonyl)amino]benzamide(100 mg, 0.205 mmol), acetone (0.075 mL), and sodium cyanoborohydride(51 mg, 0.82 mmol) yielded, after treatment with HCl, 63 mg (67%) of thetitle compound as a hydrochloride salt.

¹H-NMR; IS-MS, m/e 417 (m+1).

EXAMPLE 72 Preparation ofN-(5-Chloropyridin-2-yl)-2-[(1-cyclohexylpiperidin-4-yloxycarbonyl)amino]benzamideHydrochloride

Using a similar procedure to that described in Example 9-C,N-(5-chloropyridin-2-yl)-2-[(piperidin-4-yloxycarbonyl)amino]benzamide(100 mg, 0.205 mmol), cyclohexanone (0.106 mL, 1.02 mmol), and sodiumcyanoborohydride (51 mg, 0.82 mmol) yielded, after treatment with HCl,33 mg (33%) of the title compound as a hydrochloride salt.

¹H-NMR; IS-MS, m/e 457 (m+1).

EXAMPLE 73 Preparation ofN-(5-Chloropyridin-2-yl)-2-[(1-cyclopentylpiperidin-4-yloxycarbonyl)amino]benzamideHydrochloride

Using a similar procedure to that described in Example 9-C,N-(5-chloropyridin-2-yl)-2-[(piperidin-4-yloxycarbonyl)amino]benzamide(100 mg, 0.205 mmol), cyclopentanone (0.091 mL, 1.02 mmol), and sodiumcyanoborohydride (51 mg, 0.82 mmol) yielded, after treatment with HCl,60 mg (60%) of the title compound as a hydrochloride salt.

¹H-NMR; IS-MS, m/e 443 (m+1).

EXAMPLE 74 Preparation ofN-(5-Chloropyridin-2-yl)-2-[(1-isopropylpiperidin-4-ylmethoxycarbonyl)amino]benzamideHydrochloride

Using a similar procedure to that described in Example 9-C,N-(5-chloropyridin-2-yl)-2-[(piperidin-4-ylmethoxycarbonyl)amino]benzamide(100 mg, 0.199 mmol), acetone (0.075 mL), and sodium cyanoborohydride(50 mg, 0.80 mmol) yielded, after treatment with HCl, 25 mg of the titlecompound as a hydrochloride salt.

¹H-NMR; IS-MS, m/e 431 (m+1).

EXAMPLE 75 Preparation of2-[1-(2-Carboxypyridin-4-yl)piperidin-4-ylmethylamino]-N-(5-chloropyridin-2-yl)benzamide

Using a similar procedure to that described in Example 52,N-(5-chloropyridin-2-yl)-2-(piperidin-4-ylmethylamino)benzamide (150 mg,0.43 mmol), 4-chloropicolinic acid (95 mg, 0.60 mmol), triethylamine (87mg, 0.86 mmol), and ethanol (2 mL) yielded 50 mg (25%) of the titlecompound.

¹H-NMR, IR; IS-MS, m/e 466 (m+1); Analysis for C₂₄H₂₄ClN₅O₃(1.5H₂O):Calcd: C, 58.47; H, 5.52; N, 14.21; Found: C, 58.37; H, 5.08; N, 13.96.

EXAMPLE 76 Preparation ofN-(5-Chloropyridin-2-yl)-2-(1-isopropylpiperidin-4-ylmethoxy)benzamideHydrochloride

A.N-(5-Chloropyridin-2-yl)-2-(1-tert-butoxycarbonylpiperidin-4-ylmethoxy)benzamide

A solution of N-(5-chloropyridin-2-yl)-2-hydroxybenzamide (200 mg, 0.806mmol), 1-tert-butoxycarbonylpiperidine-4-methanol (191 mg, 0.887 mmol),and triphenylphosphine (232 mg, 0.887 mmol) in THF was treated dropwisewith a THF solution of diethyl diazodicarboxylate (DEAD) (0.14 mL, 0.887mmol in 1 mL of THF). After 16 h, the mixture was treated with anadditional equivalent of triphenylphosphine and DEAD. After 2 h, themixture was concentrated, diluted with methylene chloride, and filtered.The solid collected was the desired product (128 mg, 36%). The filtratewas purified by column chromatography (SiO₂; 4:1 hexanes:EtOAc)providing an additional 142 mg (40%) of the title compound.

¹H-NMR; IS-MS, m/e 446 (m+1); Analysis for C₂₃H₂₈ClN₃O₄: Calcd: C,61.95; H, 6.33; N, 9.42; Found: C, 61.67; H, 6.63; N, 9.33.

B. N-(5-Chloropyridin-2-yl)-2-(piperidin-4-ylmethoxy)benzamide

Using a similar procedure to that described in Example 9-B,N-(5-chloropyridin-2-yl)-2-(1-tert-butoxycarbonylpiperidin-4-ylmethoxy)benzamide(240 mg, 0.539 mmol) yielded 350 mg of the title compound as atrifluoroacetate salt which was used without further purification.

C.N-(5-Chloropyridin-2-yl)-2-(1-isopropylpiperidin-4-ylmethoxy)benzamide

Using a similar procedure to that described in Example 9-C,N-(5-chloropyridin-2-yl)-2-(piperidin-4-ylmethoxy)benzamide (100 mg,0.218 mmol) yielded, after treatment with HCl, 64 mg (70%) of the titlecompound as a hydrochloride salt.

¹H-NMR; IS-MS, m/e 388 (m+1).

EXAMPLE 77 Preparation ofN-(5-Chloropyridin-2-yl)-5-(methylsulfonylamino)-2-[1-(4-pyridinyl)piperidin-4-ylmethylamino]benzamideDihydrochloride

A. Methyl 2-Fluoro-5-nitrobenzoate

A solution of 2-fluoro-5-nitrobenzoic acid (200 mg, 1.08 mmol) in 0.7 MHCl in methanol was stirred for 5 h. The mixture was concentratedyielding 210 mg (99%) of the title compound; which was used withoutfurther purification.

¹H-NMR.

B. 1-(4-Pyridyl)piperidine-4-methylamine

A solution of 1-(4-pyridinyl)piperidine-4-methanol (5.87 g, 30.6 mmol),phthalimide (4.59 g, 31.2 mmol), and triphenylphosphine (8.10 g, 30.9mmol) in 125 mL of THF at −5° C. was treated with a solution of diethylazodicarboxylate (5.38 g, 30.9 mmol) in THF (40 mL). After 16 h, themixture was poured into EtOAc and 1 N HCl. The aqueous layer was washedwith EtOAc (2×), pH adjusted to 12 by addition of 5 N NaOH, and washedwith EtOAc (3×). The combined organic extracts were dried (K₂CO₃) andconcentrated yielding 8.45 g (86%) of crude phthalimide. The crudematerial (5.47 g, 17.0 mmol) was then treated with hydrazine hydrate(3.5 mL, 60.0 mmol) in EtOH (50 mL). The mixture was heated at 75° C.for 5 h, cooled, diluted with CH₂Cl₂ (100 mL), and cooled to 0° C. Thesolid was removed by filtration and the filtrate was concentratedyielding 3.32 g of the title compound which was used without furtherpurification.

¹H-NMR, IR; FD-MS, m/e 191 (m).

C. Methyl 5-Nitro-2-[1-(4-pyridyl)piperidin-4-ylmethylamino]benzoate

A solution of 1-(4-pyridyl)piperidine-4-methylamine (1.13 g, 5.92 mmol)and potassium carbonate (816 mg, 5.92 mmol) in dimethyl sulfoxide (12mL) was treated with methyl 2-fluoro-5-nitrobenzoate (1.18 g, 5.92mmol). After 17 h, the mixture was cooled, diluted with EtOAc, andfiltered. The filtrate was concentrated and partitioned between EtOAcand 10% HCl. The aqueous layer was washed with EtOAc (1×), pH adjusted(>10) by addition of NaOH, and washed with EtOAC (3×). The combinedextracts were washed with H₂O (5×), brine, dried (sodium sulfate), andconcentrated. The residue was purified by column chromatography (SiO₂, 1to 3% [2 N NH₃ in MeOH]:chloroform) yielding 920 mg (42%) of the titlecompound.

¹H-NMR; IS-MS, m/e 381 (m+1).

D.5-Amino-N-(5-chloropyridin-2-yl)-2-[1-(4-pyridinyl)piperidin-4-ylmethylamino]benzamide

A solution of methyl5-nitro-2-[1-(4-pyridinyl)piperidin-4-ylmethylamino]benzoate (400 mg,1.08 mmol) was treated with the magnesium salt of2-amino-5-chloropyridine [freshly prepared by the addition of methylmagnesium bromide (2.16 mmol) to a solution of 2-amino-5-chloropyridine(2.16 mmol) in THF (11 mL)] and the mixture was heated at reflux. After3 h, the mixture was cooled, sonicated, and the resulting solid (645 mg)collected by filtration. Using a similar procedure to that described inExample 2-B, the crude material was reduced to yield 370 mg of thetitled compound; which was used without further purification.

¹H-NMR.

E.N-(5-Chloropyridin-2-yl)-5-(methylsulfonylamino)-2-[1-(4-pyridinyl)piperidin-4-ylmethylamino]benzamideDihydrochloride

A solution of5-amino-N-(5-chloropyridin-2-yl)-2-[1-(4-pyridinyl)piperidin-4-ylmethylamino]benzamide(90 mg, 0.21 mmol)and diisopropyl ethylamine (0.036 mL) in methylenechloride (2 mL) was treated with methanesulfonyl chloride (0.016 mL,0.21 mmol). After 0.25 h, the mixture was concentrated and the residuepartitioned between EtOAc and water. The aqueous layer was treated with1 N NaOH and the resulting solid collected by filtration. The materialwas further purified by RPHPLC yielding the title compound as ahydrochloride salt.

¹H-NMR; IS-MS, m/e 515 (m+1); Analysis for C₂₄H₃₀N₆O₃SCl₄.0.5H₂O: Calcd:C, 45.52; H, 4.93; N, 13.27; Found: C, 45.65; H, 4.92; N, 13.36.

EXAMPLE 78 Preparation ofN-(5-Chloropyridin-2-yl)-2-[1-(cylopropylmethyl)piperidin-4-ylmethylamino]benzamide

To a small sample ofN-(5-chloropyridin-2-yl)-2-(piperidin-4-ylmethylamino)benzamide (0.034g, 0.1 mmol) weighed out in a 1 mL sealable vial, dichloroethane wasadded (300 μL), followed by excess of cyclopropanecarboxaldehyde (20μL, >0.15 mmol) and sodium triacetoxyborohydride (200 μL of a 1.5 Msolution in N-methylpyrrolidinone). The vial was capped and placed in ashaker at 70° C. overnight. After an additional 24 heat roomtemperature, methanol was added (400 μL) and the vial was shaken for afew minutes. The reaction mixture was then applied to a 2 g SCX column,washed with methanol (30 mL) and gravity-eluted with 1 N ammonia inmethanol (20 mL). The yellow fractions were combined and concentrated invacuo to a dry residue (0.040 g, >100%), which was identified as thetitle compound by LC-MS (Method A).

LC-MS: 95% pure, R_(t)=2.859 min, m/e 399.2 (m).

EXAMPLE 79 Preparation ofN-(5-Chloropyridin-2-yl)-2-[1-(pyridin-4-ylmethyl)piperidin-4-ylmethylamino]benzamide

N-(5-Chloropyridin-2-yl)-2-(piperidin-4-ylmethylamino)benzamide (0.034g, 0.1 mmol) was converted to the title compound (0.050 g, >100%) usingthe procedure described in example 78. The product was obtained as anoily residue which was further purified on silica gel. Elution withethyl acetate-methanol (9:1) followed by trituration with acetonitrileafforded a solid which was identified by LC-MS (Method A).

LC-MS: 80% pure, R_(t)=1.509 min, m/e 436.1 (m).

EXAMPLE 80 Preparation ofN-(5-Chloropyridin-2-yl)-5-fluoro-2-[1-(4-pyridinyl)piperidin-4-ylmethylamino]benzamide

Using a similar procedure to that described in Example 52,N-(5-chloropyridin-2-yl)-5-fluoro-2-(piperidin-4-ylmethyl)aminobenzamide(343 mg, 0.95 mmol), 4-chloropyridine hydrochloride (709 mg, 4.73 mmol),triethylamine (479 mg, 4.73 mmol), and ethanol (3 mL) yielded 100 mg(24%) of the title compound.

1H-NMR, IR; IS-MS, m/e 440 (m+1); Analysis for C₂₃H₂₃ClFN₅O (EtOH):Calcd: C, 61.79; H, 6.01; N, 14.4; Found: C, 61.93; H, 5.56; N, 14.68.

EXAMPLE 81 Preparation ofN-(5-Chloropyridin-2-yl)-2-(1-propylpiperidin-4-ylmethylamino)benzamide

N-(5-Chloropyridin-2-yl)-2-(piperidin-4-ylmethylamino)benzamide (0.114g, 0.33 mmol) was converted to the title compound (0.084 g, 66%) usingthe procedure described in example 78. The product was obtained as anoily residue which was further purified on silica gel. Elution withethyl acetate-2 N ammonia in methanol (95:5) followed by triturationwith diethyl ether afforded a solid which was identified by LC-MS(Method A).

LC-MS: 82% pure, R_(t)=2.682 min, m/e 387.2 (m).

EXAMPLE 82 Preparation ofN-(5-Chloropyridin-2-yl)-2-[1-(2,2-dimethylpropyl)piperidin-4-ylmethylamino]benzamide

N-(5-Chloropyridin-2-yl)-2-(piperidin-4-ylmethylamino)benzamide (0.114g, 0.33 mmol) was converted to the title compound (0.060 g, 44%) usingthe procedure described in example 78. The product was obtained as anoily residue which was further purified on silica gel. Elution withethyl acetate-2 N ammonia in methanol (95:5) followed by triturationwith diethyl ether afforded a solid which was identified by LC-MS(Method A).

LC-MS: 92% pure, R_(t)=3.626 min, m/e 415.1 (m).

EXAMPLE 83 Preparation of5-Chloro-N-(5-chloropyridin-2-yl)-2-[1-(4-pyridinyl)piperidin-4-ylmethylamino]benzamide

Using a similar procedure to that described in Example 52,5-chloro-N-(5-chloropyridin-2-yl)-2-(piperidin-4-ylmethyl)aminobenzamide(400 mg, 1.05 mmol), 4-chloropyridine hydrochloride (791 mg, 5.27 mmol),triethylamine (533 mg, 5.27 mmol), and ethanol (3 mL) yielded 70 mg(15%) of the title compound.

¹H-NMR, IR; IS-MS, m/e 456 (m+1); Analysis for C₂₃H₂₃Cl₂N₅O0.5H₂O:Calcd: C, 59.36; H, 5.20; N, 15.05; Found: C, 59.84; H, 5.14; N, 14.82.

EXAMPLE 84 Preparation of5-Chloro-N-(5-fluoropyridin-2-yl)-2-[(1-isopropylpiperidin-4-ylcarbonyl)amino]benzamideHydrochloride

A.2-[(1-boc-Piperidin-4-ylcarbonyl)amino]-5-chloro-N-(5-fluoropyridin-2-yl)benzamide

Using methods substantially equivalent to those described in example25-D,2-[(1-Boc-piperidin-4-ylcarbonyl)amino]-5-chloro-N-(5-fluoropyridin-2-yl)benzamide(0.91 g, 79%) was prepared from2-amino-5-chloro-N-(5-fluoropyridin-2-yl)benzamide and1-Boc-piperidin-4-ylcarbonyl chloride.

¹H-NMR; IS-MS, m/e 477.2 (m+1); Analysis for C₂₃H₂₆N₄O₄ClF: Calcd: C,57.92; H, 5.49; N, 11.75; Found: C, 58.04; H, 5.61; N, 11.51.

B.5-Chloro-N-(5-fluoropyridin-2-yl)-2-[(piperidin-4-ylcarbonyl)amino]benzamideTrifluoroacetate

Using methods substantially equivalent to those described in example9-B,5-chloro-N-(5-fluoropyridin-2-yl)-2-[(piperidin-4-ylcarbonyl)amino]benzamidetrifluoroacetate (0.805 g, 93%) was prepared from2-[(1-Boc-piperidin-4-ylcarbonyl)amino]-5-chloro-N-(5-fluoropyridin-2-yl)benzamide

¹H-NMR; IS-MS, m/e 377.3 (m+1).

C.5-Chloro-N-(5-fluoropyridin-2-yl)-2-[(1-isopropylpiperidin-4-ylcarbonyl)amino]benzamideHydrochloride

Using methods substantially equivalent to those described in example 27,5-chloro-N-(5-fluoropyridin-2-yl)-2-[(1-isopropylpiperidin-4-ylcarbonyl)amino]benzamidehydrochloride (0.167 g, 60%) was prepared from5-chloro-N-(5-fluoropyridin-2-yl)-2-[(piperidin-4-ylcarbonyl)amino]-benzamidetrifluoroacetate. The preparative RPHPLC (C18) purification procedurewas elution with a linear gradient of 90/10 to 55/45 (0.01%HCl/acetonitrile) over 180 min.

¹H-NMR; IS-MS, m/e 419.2 (m+1); Analysis forC₂₁H₂₄N₄O₂ClF.1.0HCl.0.8H₂O: Calcd: C, 53.69; H, 5.71; N, 11.93; Cl,15.09; Found: C, 53.52; H, 5.39; N, 11.84; Cl, 15.20.

EXAMPLE 85 Preparation ofN-(5-Chloropyridin-2-yl)-2-[1-(2-methylpyridin-4-yl)piperidin-4-ylmethylamino]benzamide

To a solution ofN-(5-chloropyridin-2-yl)-2-(piperidin-4-ylmethylamino)benzamide (0.130g, 0.38 mmol) in ethanol (10 mL) was added 4-chloro-2-picoline (0.1 mL).The reaction mixture was heated in a sealed tube for 24 hours. Thereaction mixture was concentrated and the residue was purified byRPHPLC. The pure product containing fractions were combined andlyophilized to give 155 mg (66%) of a tan powder.

¹H-NMR; FD-MS, m/e 436.3 (m+1); Analysis for C₂₄H₂₆ClN₅O.4HCl.2H₂O:Calcd: C, 46.66 ; H, 5.55 ; N, 11.34; Found: C, 47.02 ; H, 5.32 ; N,11.26.

EXAMPLE 86 Preparation of2-[1-(2-Carboxypyridin-4-yl)piperidin-4-ylmethylamino]-5-chloro-N-(5-chloropyridin-2-yl)benzamide

Using a similar procedure to that described in Example 52,5-chloro-N-(5-chloropyridin-2-yl)-2-(piperidin-4-ylmethyl)aminobenzamide(166 mg, 0.44 mmol), 4-chloropicolinic acid (103 mg, 0.66 mmol),triethylamine (89 mg, 0.88 mmol), and ethanol (3 mL) yielded 180 mg(82%) of the title compound.

¹H-NMR, IR; IS-MS, m/e 500 (m+1); Analysis for C₂₄H₂₃Cl₂N₅O₃.3.0H₂O:Calcd: C, 51.99; H, 5.27; N, 12.63; Found: C, 51.77; H, 4.94; N, 12.98.

EXAMPLE 87 Preparation ofN-(5-Chloropyridin-2-yl)-2-[(1-isopropylpyrrolidin-3-ylaminocarbonyl)amino]benzamideHydrochloride

A.2-[(1-tert-Butoxycarbonylpyrrolidin-3-ylaminocarbonyl)amino]-N-(5-chloropyridin-2-yl)benzamide

A solution of 3-amino-1-tert-butoxycarbonylpyrrolidine (200 mg, 1.08mmol; prepared from 1-tert-butoxycarbonyl-3-hydroxy-pyrrolidine using asimilar procedure to that described in Example 77-B) and triethylamine(0.38 mL) in methylene chloride (3.5 mL) was added dropwise to asolution of triphosgene (120 mg, 0.403 mmol) in methylene chloride (2mL). After complete addition, a solution of2-amino-N-(5-chloropyridin-2-yl)benzamide (242 mg, 0.983 mmol) andtriethylamine (0.38 mL) in methylene chloride (3.5 mL) was added in oneportion. After 16 h, the mixture was treated with an additionalequivalent of the isocyanate. After 1 h, the mixture was concentratedand the residue was partitioned between EtOAc and water. The organiclayer was washed with 0.5 N HCl (2×), satd sodium bicarbonate (1×),water, brine, dried with sodium sulfate, and concentrated. The residuewas purified by column chromatography (SiO₂: 40 to 50% EtOAc in hexanes)affording 160 mg (35%) of the title compound.

¹H-NMR; IS-MS, m/e 460 (m+1); Analysis for C₂₂H₂₆Cl₄N₅O₄: Calcd: C,57.45; H, 5.70; N, 15.23; Found: C, 57.27; H, 5.79; N, 15.06.

B.N-(5-Chloropyridin-2-yl)-2-[(pyrrolidin-3-ylaminocarbonyl)amino]benzamideTrifluoroacetate

Using a similar procedure to that described in Example 9-B,2-[(1-tert-butoxycarbonylpyrrolidin-3-ylaminocarbonyl)amino]-N-(5-chloropyridin-2-yl)benzamide(100 mg, 0.218 mmol) yielded the titled compound as a trifluoroacetatesalt, which was used without further purification.

¹H-NMR; IS-MS, m/e 360 (m+1).

C.N-(5-Chloropyridin-2-yl)-2-[(1-isopropylpyrrolidin-3-ylaminocarbonyl)amino]benzamideHydrochloride

Using a similar procedure to that described in Example 9-C,N-(5-chloropyridin-2-yl)-2-[(pyrrolidin-3-ylaminocarbonyl)amino]benzamidetrifluoroacetate (100 mg, 0.211 mmol) yielded, after purification of themixture by column chromatography (3% [2 N NH₃ in methanol]:chloroform)and treatment with HCl, 65 mg of the title compound as a hydrochloridesalt.

¹H-NMR; IS-MS, m/e 402 (m+1).

EXAMPLE 88 Preparation of2-[(4-Aminocyclohexylcarbonyl)amino]-5-chloro-N-(5-chloropyridin-2-yl)benzamide

A. 4-(tert-Butoxycarbonylamino)cyclohexanecarboxylic Acid

To a suspension of of 4-aminocyclohexanecarboxylic acid (9.3 g, 65mmol), potassium carbonate (9.88 g, 71.5 mmol), di-t-butyl dicarbonate(15.6 g, 71.5 mmol) and acetone (500 ml) was added water (100 mL). Thereaction was stirred for 16 hours and the organic solvent was removed invacuo. A solution of 3:1 hexane:ether (8 mL) was added to the reactionmixture and then the mixture was acidified with saturated citric acid.The solid was filtered with water and 3:1 hexane:ether washes. Theproduct was air dried and vacuum dried to give the title compound as awhite solid (14.7 g, 93%).

¹H-NMR (300 MHz, CDCl₃): 4.57 (br s, 0.7H), 4.38 (br s, 0.3H), 3.61 (brs, 0.7H), 3.20 (br s, 0.3H), 2.52 (br s, 1H), 2.00-2.16 (m, 1H), 1.42(s, 9H), 1.00-2.00 (m, 7H). IS-MS, m/e: 244.2 (m+1).

B.2-[[4-(tert-Butoxycarbonylamino)cyclohexylcarbonyl]-amino]-5-chloro-N-(5-chloropyridin-2-yl)benzamide

Using a procedure similar to that described in example 34-A,2-[[4-(tert-butoxycarbonylamino)cyclohexylcarbonyl]amino]-5-chloro-N-(5-chloropyridin-2-yl)benzamide(2.91 g, 52%) was prepared from2-amino-N-(5-methylpyridin-2-yl)benzamide and4-(tert-butoxycarbonylamino)cyclohexanecarboxylic acid.

¹H-NMR (400 MHz, DMSO-d₆): δ 11.10 (s, 1H); 10.24 (s, 1H); 8.41 (d,J=2.0 Hz, 1H); 8.10 (d, J=9.2 Hz, 1H); 8.01 (d, J=9.2 Hz, 1H); 7.93 (dd,J=2.4, 9.2 Hz, 1H); 7.78 (d, J=2.4 Hz, 1H); 7.55 (dd, J=2.4, 8.8 Hz,1H); 6.69 (m, 1H); 3.36 (m, 1H); 2.37 (m, 1H); 1.79-1.45 (m, 8H); 1.33(s, 9H). MS-FIA m/e: 507.2 (m+1). Analysis for C₂₄H₂₈N₄O₄Cl₂.0.35CH₂Cl₂:Calcd: C, 54.80; H, 5.34; N, 10.35; Found: C, 54.58; H, 5.25; N, 10.57.

C.2-[(4-Aminocyclohexylcarbonyl)amino]-5-chloro-N-(5-chloropyridin-2-yl)benzamide

2-[[4-(tert-Butoxycarbonylamino)cyclohexylcarbonyl]-amino]-5-chloro-N-(5-chloropyridin-2-yl)benzamide(2.90 g, 5.71 mmol) was dissolved in TFA (10 mL). After 5 minutes, thereaction was concentrated in vacuo. The residue was diluted withmethylene chloride and methanol. The organics were washed with saturatedaqueous sodium carbonate (2×50 mL) and water (50 mL). The organic layerwas dried over sodium sulfate, filtered and concetrated to give thetitle product (1.86 g, 4.56 mmol, 80%) as a white solid.

¹H-NMR (300 MHz, DMSO-d₆): δ 8.33 (s, 1H); 8.13 (m, 2H); 7.85 (s, 1H);7.83 (d, J=9.9 Hz, 1H); 7.46 (d, J=8.4 Hz, 1H); 2.91 (m, 1H); 2.39 (m,1H); 1.87 (m, 2H); 1.48 (m, 6H). MS-FIA m/e: 407.3 (m+1). Analysis forC₁₉H₂₀N₄O₂Cl₂: Calcd: C, 56.03; H, 4.95; N, 13.76; Found: C, 55.91; H,5.05; N, 13.58.

EXAMPLE 89 Preparation of5-Chloro-N-(5-chloropyridin-2-yl)-2-[4-(N,N-dimethylamino)cyclohexylcarbonylamino]benzamide

Using a procedure similar to example 9-C,5-chloro-N-(5-chloropyridin-2-yl)-2-[4-(N,N-dimethylamino)cyclohexylcarbonylamino]benzamide(121 mg, 38%) was prepared from.2-[(4-aminocyclohexylcarbonyl)amino]-5-chloro-N-(5-chloropyridin-2-yl)benzamide

¹H-NMR (400 MHz, DMSO-d₆): δ 8.38 (s, 1H); 8.10 (d, J=8.8 Hz, 1H); 7.96(m, 1H); 7.90 (m, 1H); 7.83 (d, J=3.2 Hz, 1H); 7.51 (d, J=9.2 Hz, 1H);3.29 (m, 1H); 2.47 (m, 1H); 1.86-1.38 (m, 8H); MS-FD m/e: 435.1 (m+1);Analysis for C₂₁H₂₄N₄O₂Cl₂.0.2CH₂Cl₂: Calcd: C, 55.45; H, 5.31; N,12.20; Found: C, 55.76; H, 5.29; N, 12.01.

EXAMPLE 90 Preparation of5-Chloro-N-(5-chloropyridin-2-yl)-2-[(1-cyclopentylpiperidin-4-ylcarbonyl)amino]benzamideHydrochloride

Using methods substantially equivalent to those described in example 27,5-chloro-N-(5-chloropyridin-2-yl)-2-[(1-cyclopentylpiperidin-4-ylcarbonyl)amino]benzamidehydrochloride (0.122 g, 25%) was prepared from5-chloro-N-(5-chloropyridin-2-yl)-2-[(piperidin-4-ylcarbonyl)amino]-benzamidetrifluoroacetate and cyclopentanone. The preparative RPHPLC (C18)purification procedure was elution with a linear gradient of 80/20 to50/50 (0.01% HCl/acetonitrile) over 180 min.

¹H-NMR; IS-MS, m/e 461.3 (m+1); Analysis forC₂₃H₂₆N₄O₂Cl₂.1.2HCl.1.7H₂O: Calcd: C, 51.56; H, 5.76; N, 10.46; Cl,21.18; Found: C, 51.78; H, 5.82; N, 10.30; Cl, 21.24.

EXAMPLE 91 Preparation of5-Chloro-N-(5-chloropyridin-2-yl)-2-[[1-(4-pyridinylmethyl)piperidin-4-ylcarbonyl]amino]benzamideHydrochloride

Using methods substantially equivalent to those described in example 27,5-chloro-N-(5-chloropyridin-2-yl)-2-[[1-(4-pyridinylmethyl)piperidin-4-ylcarbonyl]amino]-benzamidehydrochloride (0.21 g, 40%) was prepared from5-chloro-N-(5-chloropyridin-2-yl)-2-[(piperidin-4-ylcarbonyl)amino]benzamidetrifluoroacetate and pyridine-4-carboxaldehyde. The preparative RPHPLC(C18) purification procedure was elution with a linear gradient of 80/20to 50/50 (0.01% HCl/acetonitrile) over 180 min.

¹H-NMR; IS-MS, m/e 484.4 (m+1); Analysis forC₂₄H₂₃N₅O₂Cl₂.2.6HCl.1.6H₂O: Calcd: C, 47.41; H, 4.77; N, 11.52; Cl,26.82; Found: C, 47.40; H, 4.41; N, 11.16; Cl, 26.89.

EXAMPLE 92 Preparation of5-Chloro-N-(5-chloropyridin-2-yl)-2-[[1-(4-thianyl)piperidin-4-ylcarbonyl]amino]benzamideHydrochloride

Using methods substantially equivalent to those described in example 27,5-chloro-N-(5-chloropyridin-2-yl)-2-[[1-(4-thianyl)piperidin-4-ylcarbonyl]amino]benzamidehydrochloride (0.080 g, 15%) was prepared from5-chloro-N-(5-chloropyridin-2-yl)-2-[(piperidin-4-ylcarbonyl)amino]-benzamidetrifluoroacetate and tetrahydrothiopyran-4-one The preparative RPHPLC(C18) purification procedure was elution with a linear gradient of 80/20to 50/50 (0.01% HCl/acetonitrile) over 180 min.

¹H-NMR; IS-MS, m/e 493.2 (m+1); Analysis for C₂₃H₂₆N₄O₂Cl₂S.HCl.0.1H₂O:Calcd: C, 51.95; H, 5.16; N, 10.54; Cl, 20.00; Found: C, 51.87; H, 5.03;N, 10.57; Cl, 20.24.

EXAMPLE 93 Preparation of2-[1-(2-Carboxypyridin-4-yl)piperidin-4-ylmethylamino]-N-(5-chloropyridin-2-yl)-5-fluorobenzamide

Using a similar procedure to that described in Example 52,N-(5-chloropyridin-2-yl)-5-fluoro-2-(piperidin-4-ylmethyl)aminobenzamide(200 mg, 0.55 mmol), 4-chloropicolinic acid (130 mg, 0.83 mmol),triethylamine (111 mg, 1.10 mmol), and ethanol (4 mL) yielded 120 mg(45%) of the title compound.

¹H-NMR, IR; IS-MS, m/e 485 (m+1); Analysis for C₂₄H₂₃ClFN₅O₃(2.5H₂O):Calcd: C, 54.50; H, 5.34; N, 13.23; Found: C, 54.32; H, 4.56; N, 12.90.

EXAMPLE 94 Preparation of2-(4-Acetylaminobenzyl)amino-5-chloro-N-(5-chloropyridin-2-yl)benzamide

To a small sample of 2-amino-5-chloro-N-(5-chloropyridin-2-yl)benzamide(0.01 g, 0.035 mmol) weighed out in a sealable vial toluene was added(200 μL), followed by 4-acetamidobenzaldehyde (0.006 g, 0.035 mmol) andpyridinium p-toluenesulfonate (catalytic amount). A few molecular sieveswere added; then the vial was sealed and placed in a shaker at 75° C.After 18 h, the reaction mixture was treated with borane-trimethylaminecomplex (100 μL of a 1 M solution in acetic acid) and the vial wasplaced in the shaker at room temperature for an additional 5 h. Thereaction mixture was then diluted with methanol and applied to a 0.5 gSCX column, washed with methanol and gravity-eluted with 1 N ammonia inmethanol. The product fractions were combined and concentrated in vacuoto a residue which was triturated in acetonitrile to provide the titlecompound as a yellowish powder (0.015 g, 100%) in 98% purity by LC-MS(method A).

LC-MS: 98% pure, R_(t)=6.647 min, m/e 429.2 (m).

EXAMPLE 95 Preparation of2-[[4-(1-Azetedinyl)piperidin-1-ylcarbonyl]-amino]-N-(5-chloropyridin-2-yl)benzamide

A. Methyl 2-(1,4-Dioxa-8-azaspiro[4.5]decan-8-ylcarbonyl)aminobenzoate

A solution of 2-carbomethoxyphenyl isocyanate (10.0 g, 56.5 mmol) inmethylene chloride (300 mL) was treated with the ethlene glycol ketal of4-piperidinone (7.93 mL. 62.1 mmol). After 17 h, the mixture wasconcentrated and the residue partitioned between EtOAc and 1 N HCl. Theorganic layer was washed with 1 N HCl (1×), 1 N NaOH (2×), brine, driedwith sodium sulfate, and concentrated yielding 17.2 g of the titlecompound; which was used without further purification.

¹H-NMR.

B. 2-(1,4-Dioxa-8-azaspiro[4.5]decan-8-ylcarbonyl)aminobenzoic Acid

A solution of methyl2-(1,4-dioxa-8-azaspiro[4.5]decan-8-ylcarbonyl)aminobenzoate (2.00 g,6.25 mmol) in dioxane (30 mL) was treated with 5 N NaOH (12.5 mL). After1 h, the mixture was poured into EtOAc and water, and the aqueous layerwas washed with EtOAc. The pH of the aqueous layer was then adjusted to2-3 by addition of 5 N HCl and washed with EtOAc (3×). The combinedorganic layers were washed with brine, dried with sodium sulfate, andconcentrated, yielding the title compound; which was used withoutfurther purification.

¹H-NMR; IS-MS, m/e 307 (m+1).

C. 2-(1,4-Dioxa-8-azaspiro[4.5]decan-8-yl)-4H-3,1-benzoxazin-4-one

Using a similar procedure to that described in Example 51-C,2-(1,4-dioxa-8-azaspiro[4.5]decan-8-ylcarbonyl)aminobenzoic acid (1.91g, 6.25 mmol) yielded 1.36 g of the title compound; which was usedwithout further purification.

¹H-NMR; IS-MS, m/e 288 (m); Analysis for C₁₅H₁₆N₂O₄: Calcd: C, 62.49; H,5.59; N, 9.72; Found: C, 63.17; H, 5.66; N, 9.94.

D.N-(5-Chloropyridin-2-yl)-2-(1,4-dioxa-8-azaspiro[4.5]decan-8-ylcarbonyl)aminobenzamide

Using a similar procedure to that described in example 51-D,2-(1,4-dioxa-8-azaspiro[4.5]decan-8-yl)-4H-3,1-benzoxazin-4-one (1.30 g,4.51 mmol) and 2-amino-5-chloropyridine (573 mg, 4.51 mmol) yielded,after recrystallization from EtOAc, 880 mg (47%) of the titled compound.

¹H-NMR; IS-MS, m/e 417 (m+1); Analysis for C₂₀H₂₁ClN₄O₄: Calcd: C,57.63; H, 5.08; N, 13.44; Found: C, 58.10; H, 4.97; N, 13.78.

E.N-(5-Chloropyridin-2-yl)-2-(4-oxopiperidin-1-ylcarbonyl)aminobenzamide

A solution ofN-(5-chloropyridin-2-yl)-2-(1,4-dioxa-8-azaspiro[4.5]decan-8-ylcarbonyl)aminobenzamide(120 mg, 0.289 mmol) in dioxane (1 mL) and water (0.25 mL) was treatedwith 12 N HCl (0.25 mL). After 1.5 h, the mixture was poured into EtOAcand water. The organic layer was washed with satd sodium bicarbonate(2×), brine, dried with sodium sulfate, and concentrated yielding 100 mgof the title compound; which was used without further purification.

¹H-NMR; IS-MS, m/e 373 (m+1).

F.2-[[4-(1-Azetedinyl)piperidin-1-ylcarbonyl]amino]-N-(5-chloropyridin-2-yl)benzamide

Using a similar procedure to that described in Example 9-C,N-(5-chloropyridin-2-yl)-2-(4-oxopiperidin-1-ylcarbonyl)aminobenzamide(100 mg, 0.268 mmol) and azetidine (0.036 mL, 0.54 mmol) yielded thetitle compound.

¹H-NMR; IS-MS, m/e 414 (m+1).

EXAMPLE 96 Preparation ofN-(5-Chloropyridin-2-yl)-2-[[4-(1-pyrrolidinyl)piperidin-1-ylcarbonyl]amino]benzamide

Using a similar procedure to that described in Example 9-C,N-(5-chloropyridin-2-yl)-2-(4-oxopiperidin-1-ylcarbonyl)aminobenzamide(100 mg, 0.268 mmol) and pyrolidine (0.045 mL, 0.54 mmol) yielded thetitle compound.

¹H-NMR; IS-MS, m/e 428 (m+1).

EXAMPLE 97 Preparation ofN-(5-Chloropyridin-2-yl)-2-[1-(2-methoxycarbonylpyridin-4-yl)piperidin-4-ylmethyl)amino]benzamide

A slurry of2-[1-(2-carboxypyridin-4-yl)piperidin-4-ylmethylamino]-N-(5-chloropyridin-2-yl)benzamide(100 mg, 0.21 mmol) in 4:1 methylene chloride:methanol (10 mL) wastreated with trimethylsilyl diazomethane (2 M solution in hexanes, 0.21mL, 0.42 mmol). After 1 h, the mixture was concentrated and the residuewas purified by column chromatography (SiO₂: 1:1 methylenechloride:EtOAc) yielding 50 mg (49%) of the title compound.

¹H-NMR, IR; IS-MS, m/e 480 (m+1); Analysis for C₂₅H₂₆ClN₅O₃(1.0H₂O):Calcd: C, 60.30; H, 5.67; N, 14.06; Found: C, 60.30; H, 5.46; N, 13.68.

EXAMPLE 98 Preparation ofN-(5-Chloropyridin-2-yl)-2-[[4-(N,N-dimethylmino)piperidin-1-ylcarbonyl]amino]benzamideHydrochloride

Using a similar procedure to that described in Example 27,N-(5-chloropyridin-2-yl)-2-(4-oxopiperidin-1-ylcarbonyl)aminobenzamide(100 mg, 0.268 mmol) and dimethylamine (2.0 M solution, 2.7 mL, 5.4mmol) yielded, after treatment with HCl, 100 mg of the title compound asa hydrochloride salt.

¹H-NMR; IS-MS, m/e 402 (m+1).

EXAMPLE 99 Preparation of5-Chloro-2-(1-isopropylpiperidin-4-ylmethylamino)-N-(5-methylpyridin-2-yl)benzamide

A.5-Chloro-N-(5-methylpyridin-2-yl)-2-(piperidin-4-ylmethylamino)benzamide

Utilizing a procedure analogous to the one described in example 60-A,5-chloro-N-(5-methylpyridin-2-yl)-2-(piperidin-4-ylmethylamino)benzamidewas prepared from 1-Boc-piperidine-4-carboxaldehyde (3.8 g, 11.5 mmol)and 2-amino-5-chloro-N-(5-methylpyridin-2-yl)benzamide (3 g, 11.5 mmol).The crude reaction product was purified on silica gel. Elution withethyl acetate-hexanes (1:2) provided the title compound (0.48 g, 10%),which was taken on directly to the next step without furtherpurification.

¹H-NMR; FD-MS, m/e 359.1 (m).

B.5-Chloro-2-(1-isopropylpiperidin-4-ylmethylamino)-N-(5-methylpyridin-2-yl)benzamide

Using the procedure described in example 48,5-chloro-N-(5-methylpyridin-2-yl)-2-(piperidin-4-ylmethylamino)benzamidefrom above (0.448 g, 1.3 mmol) was converted into the title compound(0.500 g, 100%). The crude product was triturated in acetonitrile,providing analytically pure material which was identified by LC-MS(Method B).

¹H-NMR; mp 147.0-148.4° C.; LC-MS: 96% pure, R_(t)=5.044 min, m/e 401.3(m); FTIR; Analysis for C₂₂H₂₉N₄OCl.0.25MeOH: Calcd: C, 65.35; H, 7.39;N, 13.70; Found: C, 65.01; H, 7.15; N, 13.49.

EXAMPLE 100 Preparation of5-Chloro-N-(5-chloropyridin-2-yl)-2-[[4-(1-pyrrolidinyl)cyclohexylcarbonyl]amino]benzamideHydrochloride

2-[(4-Aminocyclohexylcarbonyl)amino]-5-chloro-N-(5-chloropyridin-2-yl)benzamide(300 mg, 0.74 mmol) was diluted with dimethylformamide (8 mL). Potassiumcarbonate (307 mg, 2.22 mmol) and 1,4-dibromobutane (88 mL, 0.74 mmol)were added. The reaction was heated to 80° C. over the weekend. Thereaction was cooled to room temperature, diluted with ethyl acetate (50mL) and washed with water (5×10 mL). The ethyl acetate layer was driedover sodium sulfate, filtered and concentrated. The crude material waspurified by HPLC to give 284 mg (77%) of the title compound as a whitesolid.

¹H-NMR (300 MHz, DMSO-d₆): δ 8.44 (d, J=2.3 Hz, 1H); 8.13 (d, J=9.0 Hz,1H); 7.97 (m, 1H); 7.92 (s, 1H); 7.59 (dd, J=2.4, 8.9 Hz, 1H); 3.12 (m,1H); 2.95 (m, 2H); 2.64 (t, J=4.3 Hz, 1H); 2.07-1.52 (m, 14H). MS-FIAm/e: 461.3 (m+1). Analysis for C₂₃H₂₆N₄O₂Cl₂.0.25HCl: Calcd: C, 58.71;H, 5.62; N, 11.91; Found: C, 58.75; H, 5.33; N, 12.20.

EXAMPLE 101 Preparation ofN-(5-Chloropyridin-2-yl)-2-[(4-isopropylpiperazin-1-ylcarbonyl)amino]-5-methylbenzamideHydrochloride

A. 2-[(4-boc-Piperazin-1-ylcarbonyl)amino]-5-methylbromobenzene

Using methods substantially equivalent to those described in example51-A, 2-[(4-Boc-piperazin-1-yl-carbonyl)amino]-5-methylbromobenzene (7.9g, 73%) was prepared from 4-Boc-piperazine and 2-bromo-4-methylaniline

¹H-NMR; IS-MS, m/e 398.1 (m+1).

B. 2-[(4-boc-Piperazin-1-ylcarbonyl)amino]-5-methylbenzoic Acid

Using methods substantially equivalent to those described in example51-B, 2-[(4-Boc-piperazin-1-ylcarbonyl)amino]-5-methylbenzoic acid (1.1g, 60%) was prepared from2-[(4-Boc-piperazin-1-ylcarbonyl)amino]-5-methylbromobenzene

C. 2-(4-boc-Piperazin-1-yl)-6-methyl-4H-3,1-benzoxazin-4-one

Using methods substantially equivalent to those described in example51-C, 2-(4-Boc-piperazin-1-yl)-6-methyl-4H-3,1-benzoxazin-4-one (0.88 g,93%) was prepared fromN-(5-chloropyridin-2-yl)-2-[(piperazin-1-ylcarbonyl)amino]-5-methylbenzoicacid.

¹H-NMR; IS-MS, m/e 346.2 (m+1); Analysis for C₁₈H₂₃N₃O₄: Calcd: C,62.59; H, 6.71; N, 12.17; Found: C, 62.32; H, 6.67; N, 12.15.

D.2-[(1-boc-Piperazin-1-ylcarbonyl)amino]-N-(5-chloropyridin-2-yl)-5-methylbenzamide

Using methods substantially equivalent to those described in example51-D,2-[(1-Boc-piperazin-1-ylcarbonyl)amino]-N-(5-chloropyridin-2-yl)-5-methylbenzamide(0.51 g, 50%) was prepared from2-(4-Boc-piperazin-1-yl)-6-methyl-4H-3,1-benzoxazin-4-one

¹H-NMR; IS-MS, m/e 474.1 (m+1); Analysis for C₂₃H₂₈N₅O₄Cl: Calcd: C,58.29; H, 5.95; N, 14.78; Found: C, 58.30; H, 5.68; N, 14.85.

E.N-(5-Chloropyridin-2-yl)-2-[(piperazin-1-ylcarbonyl)amino]-5-methylbenzamideTrifluoroacetate

Using methods substantially equivalent to those described in example9-B,N-(5-chloropyridin-2-yl)-2-[(piperazin-1-ylcarbonyl)amino]-5-methylbenzamidetrifluoroacetate (0.391 g, 95%) was prepared from2-[(1-Boc-piperazin-1-ylcarbonyl)amino]-N-(5-chloropyridin-2-yl)-5-methylbenzamide

¹H-NMR; IS-MS, m/e 374.2 (m+1); Analysis for C₁₈H₂₀N₅O₂Cl.TFA: Calcd: C,49.24; H, 4.34; N, 14.35; F, 11.68; Found: C, 48.82; H, 3.84; N, 14.00;F, 11.95.

F.N-(5-Chloropyridin-2-yl)-2-[(4-isopropylpiperazin-1-ylcarbonyl)amino]-5-methylbenzamideHydrochloride

Using methods substantially equivalent to those described in example 27,N-(5-chloropyridin-2-yl)-2-[(4-isopropylpiperazin-1-ylcarbonyl)amino]-5-methylbenzamidehydrochloride (55 mg, 17%) was prepared fromN-(5-chloropyridin-2-yl)-2-[(piperazin-1-ylcarbonyl)amino]-5-methylbenzamidetrifluoroacetate and acetone. The preparative RPHPLC (C18) purificationprocedure was elution with a linear gradient of 80/20 to 50/50 (0.01%HCl/acetonitrile) over 180 min.

¹H-NMR; IS-MS, m/e 416.3 (m+1); Analysis for C₂₁H₂₆N₅O₂Cl.1.7HCl.2.2H₂O:Calcd: C, 48.73; H, 6.25; N, 13.53; Cl, 18.50; Found: C, 49.10; H, 5.98;N, 13.17; Cl, 18.62.

EXAMPLE 102 Preparation of5-Chloro-N-(5-chloropyridin-2-yl)-2-[[1-(1-phenylethyl)piperidin-4-ylcarbonyl]amino]benzamideHydrochloride

To a stirred solution of5-chloro-N-(5-chloropyridin-2-yl)-2-[(4-piperidinylcarbonyl)amino]benzamidetrifluoroacetate (0.2 g, 0.39 mmol) and triethylamine (0.115 mL, 0.82mmol) in N,N-dimethylformamide (5 mL) was added (1-bromoethyl)benzene(0.065 mL, 0.47 mmol). After stirring for 72 h at room temperature, thesolution was passed through an SCX column (2 N ammonia in methanol) andconcentrated in vacuo. The preparative RPHPLC (C18) purificationprocedure was elution with a linear gradient of 80/20 to 50/50 (0.01%HCl/acetonitrile) over 180 min. The product containing fractions werecombined and lyophilized to give 0.091 g (44%) of the title compound asa white solid.

¹H-NMR; IS-MS, m/e 497.2; Analysis for C₂₆H₂₆N₄O₂Cl₂.1.1HCl0.3H₂O:Calcd: C, 57.52; H, 5.14; N, 10.32; Cl, 20.24; Found: C, 57.52; H, 4.99;N, 10.35; Cl, 20.35.

EXAMPLE 103 Preparation ofN-(5-Chloropyridin-2-yl)-2-[[1-[1-(4-pyridinyl)ethyl]piperidin-4-ylmethyl]amino]benzamide

To a small sample ofN-(5-chloropyridin-2-yl)-2-(piperidin-4-ylmethylamino)benzamide (0.03 g,0.1 mmol) weighed out in a 1 mL sealable vial, excess 4-acetylpyridinewas added (100 μL, ca. 1 mmol) followed by sodium cyanoborohydride (360μL of a 1 M solution in tetrahydrofuran) and methanol-acetic acid(95:5). The vial was capped and placed in a shaker at 50° C. for severaldays until reasonable conversion by TLC was evident. The reactionmixture was then diluted with methanol, shaken well for several minutes,and allowed to stand for 0.5 h before applying it to a 2 g SCX column.After washing well with methanol, the product was gravity-eluted fromthe column with 2 M ammonia in methanol. The product fractions werecombined and concentrated in vacuo to a residue which was triturated inacetonitrile, giving rise to the title compound as a powdery solid (0.03g, 74%) in >98% purity by HPLC.

FD-MS, m/e 450.2 (m).

EXAMPLE 104 Preparation ofN-(5-Chloropyridin-2-yl)-3-[[1-[1-(3-thiophenyl)ethyl]piperidin-4-ylmethyl]amino]benzamide

Using the procedure described in example 103,N-(5-chloropyridin-2-yl)-2-(piperidin-4-ylmethylamino)benzamide (0.03 g,0.1 mmol) was converted to the title compound (0.038 g, 93%), which wasidentified by LC-MS (Method A).

LC-MS: 87% pure, R_(t)=3.825 min, m/e 455.2 (m).

EXAMPLE 105 Preparation ofN-(5-Chloropyridin-2-yl)-2-[1-[2-(N-hydroxycarbamimidoyl)pyridin-4-yl]piperidin-4-ylmethyl]amino]-benzamide

A solution ofN-(5-chloropyridin-2-yl)-2-[1-(3-cyanopyridin-4-yl)piperidin-4-ylmethylamino]benzamide(50 mg, 0.11 mmol) and triethylamine (22 mg, 0.22 mmol) in ethanol (5mL) was treated with hydroxylamine hydrochloride (12 mg, 0.17 mmol).After 16 h, the mixture was concentrated and the residue was purified bycolumn chromatography (SiO₂; 5% methanol in methylene chloride) yielding40 mg (75%) of the title compound.

¹H-NMR, IR; IS-MS, m/e 480 (m+1); Analysis for C₂₄H₂₆ClN₇O₂: Calcd: C,60.06; H, 5.46; N, 20.43; Found: C, 59.57; H, 5.64; N, 19.61.

EXAMPLE 106 Preparation ofN-(5-Chloropyridin-2-yl)-5-fluoro-2-[(4-isopropylpiperazin-1-ylcarbonyl)amino]benzamideHydrochloride

A. 2-[(4-boc-Piperazin-1-ylcarbonyl)amino]-5-fluorobromobenzene

By methods substantially equivalent to those described in example 51-A,2-[(1-Boc-piperazin-4-ylcarbonyl)amino]-5-fluorobromobenzene (6.4 g,59%) was prepared from 2-bromo-4-fluoroaniline

¹H-NMR; IS-MS, m/e 402.2 (m−); Analysis for C₁₆H₂₁N₃O₃BrF: Calcd: C,47.77; H, 5.26; N, 10.45; Found: C, 47.77; H, 5.00; N, 10.52.

B. 2-[(4-boc-Piperazin-1-ylcarbonyl)amino]-5-fluorobenzoic Acid

By methods substantially equivalent-to those described in example 51-B,2-[(4-Boc-piperazin-1-ylcarbonyl)amino]-5-fluorobenzoic acid (1.68 g,46%) was prepared from2-[(4-Boc-piperazin-1-ylcarbonyl)amino]-5-fluorobromobenzene

¹H-NMR; IS-MS, m/e 368.2 (m+1); Analysis for C₁₇H₂₂N₃O₅F: Calcd: C,55.58; H, 6.04; N, 11.44; Found: C, 56.34; H, 6.03; N, 11.46.

C. 2-(4-boc-Piperazin-1-yl)-6-fluoro-4H-3,1-benzoxazin-4-one

By methods substantially equivalent to those described in example 51-C,2-[4-Boc-piperazin-1-yl]-6-fluoro-4H-3,1-benzoxazin-4-one (1.35 g, 94%)was prepared from2-[(4-Boc-piperazin-1-ylcarbonyl)amino]-5-fluorobenzoic acid.

¹H-NMR; FD-MS, m/e 349 (m); Analysis for C₁₇H₂₀N₃O₄F: Calcd: C, 58.45;H, 5.77; N, 12.03; Found: C, 58.11; H, 5.61; N, 11.35.

D.2-[(4-boc-piperazin-1-ylcarbonyl)amino]-N-(5-chloropyridin-2-yl)-5-fluorobenzamide

By methods substantially equivalent to those described in example 51-D,2-[(4-Boc-piperazin-1-ylcarbonyl)amino]-N-(5-chloropyridin-2-yl)-5-fluorobenzamide(1.35 g, 77%) was prepared from2-[4-Boc-piperazin-1-yl]-6-fluoro-4H-3,1-benzoxazin-4-one

¹H-NMR; IS-MS, m/e 478.2 (m+1); Analysis for C₂₂H₂₅N₅O₄ClF: Calcd: C,55.29; H, 5.27; N, 14.65; Found: C, 55.57; H, 5.27; N, 14.58.

E.N-(5-Chloropyridin-2-yl)-5-fluoro-2-[(piperazin-1-ylcarbonyl)amino]benzamideTrifluoroacetate

By methods substantially equivalent to those described in example 9-B,N-(5-chloropyridin-2-yl)-5-fluoro-2-[(piperazin-1-ylcarbonyl)amino]benzamidetrifluoroacetate (0.96 g, 93%) was prepared from2-[(4-Boc-piperazin-1-ylcarbonyl)amino]-N-(5-chloropyridin-2-yl)-5-fluorobenzamide

¹H-NMR; IS-MS, m/e 378.4 (m+1); Analysis for C₁₇H₁₇N₅O₂ClF: Calcd: C,46.40; H, 3.69; N, 14.24; Found: C, 46.22; H, 3.66; N, 13.94.

F.N-(5-Chloropyridin-2-yl)-5-fluoro-2-[(4-isopropylpiperazin-1-ylcarbonyl)amino]benzamideHydrochloride

By methods substantially equivalent to those described in example 27,N-(5-chloropyridin-2-yl)-5-fluoro-2-[(4-isopropylpiperazin-1-ylcarbonyl)amino]benzamidehydrochloride (0.11 g, 20%) was prepared fromN-(5-chloropyridin-2-yl)-5-fluoro-2-[(piperazin-1-ylcarbonyl)amino]benzamidetrifluoroacetate. The product was purified by preparative RPHPLC (C18),eluting with a linear gradient from 80/20 through 50/50 (0.01%HCl/acetonitrile) over 180 min.

¹H-NMR; IS-MS, m/e 420.2 (m+1); Analysis forC₂₀H₂₃N₅O₂ClF.1.3HCl.0.2H₂O: Calcd: C, 51.01; H, 5.29; N, 14.87; Cl,17.32; Found: C, 51.13; H, 5.46; N, 14.53; Cl, 17.32.

EXAMPLE 107 Preparation ofN-(5-Chloropyridin-2-yl)-2-[(4-isopropylpiperazin-1-ylcarbonyl)amino]benzamideHydrochloride

A. Methyl 2-[4-boc-Piperazine-1-ylcarbonyl]aminobenzoate

To a stirring solution of 2-methoxycarbonylphenyl isocyanate (5.44 g,30.71 mmol) in 1,2-dichloroethane (30 mL) was added Boc-piperazine (5.72g, 30.71 mmol). After 1.5 h, the solvent was removed in vacuo and thesolid residue was suspended in diethyl ether with vigorous stirring,then filtered and dried to give 6.15 g (55%) of a white solid. A secondcrop was isolated by adding hexanes to the mother liquor. Theprecipitate was again filtered and dried in vacuo to give 3.32 g (30%)of a white solid.

¹H-NMR; IS-MS, m/e 364.3 (m+1).

B. 2-[4-boc-Piperazine-1-ylcarbonyl]aminobenzoic Acid

To a stirring solution of methyl2-[4-Boc-piperazine-1-ylcarbonyl]aminobenzoate (2.42 g, 6.7 mmol) inmethanol (15 mL) was added 5 N sodium hydroxide (15 mL). After 45 min,the solution was partially concentrated in vacuo to a volume of about 10mL and the solution was diluted with water and washed with diethylether. The aqueous phase was then acidified with conc HCl and extractedwith ethyl acetate. The ethyl acetate solution was then washed withbrine, dried with MgSO₄, filtered and concentrated in vacuo to give 2.03g (87%) of an off-white solid.

¹H-NMR; IS-MS, m/e 350.4 (m+1).

C. 2-[4-boc-Piperazine-1-yl]-4H-3,1-benzoxazin-4-one

By methods substantially equivalent to those described in example 51-C,2-[4-Boc-piperazine-1-yl]-4H-3,1-benzoxazin-4-one (1.76 g, 96%) wasprepared from 2-[4-Boc-piperazine-1-ylcarbonyl]aminobenzoic acid.

¹H-NMR; IS-MS, m/e 332.2; Analysis for C₁₇H₂₁N₃O₄: Calcd: C, 61.62; H,6.39; N, 12.68; Found: C, 61.92; H, 6.36; N, 12.75.

D.2-[(4-boc-Piperazin-1-ylcarbonyl)amino]-N-(5-chloropyridin-2-yl)benzamide

By methods substantially equivalent to those described in example 51-D,2-[(4-Boc-piperazin-1-ylcarbonyl)amino]-N-(5-chloropyridin-2-yl)benzamide(0.87 g, 90%) was prepared from2-[4-Boc-piperazine-1-yl]-4H-3,1-benzoxazin-4-one

¹H-NMR; IS-MS, m/e 460.0.

E. N-(5-Chloropyridin-2-yl)-2-(piperazin-1-ylcarbonyl)amino]benzamideTrifluoroacetate

By methods substantially equivalent to those described in example 9-B,N-(5-chloropyridin-2-yl)-2-[(piperazin-1-ylcarbonyl)amino]benzamidetrifluoroacetate (0.62 g, 86%) was prepared from2-[(4-Boc-piperazin-1-ylcarbonyl)amino]-N-(5-chloropyridin-2-yl)benzamide

¹H-NMR; IS-MS, m/e 360.2 (m+1).

F.N-(5-Chloropyridin-2-yl)-2-[(4-isopropylpiperazin-1-ylcarbonyl)amino]benzamideHydrochloride

By methods substantially equivalent to those described in example 27,N-(5-chloropyridin-2-yl)-2-[(4-isopropylpiperazin-1-ylcarbonyl)amino]benzamidehydrochloride (0.155 g, 33%, 97% pure by RPHPLC analysis) was preparedfromN-(5-chloropyridin-2-yl)-2-[(piperazin-4-ylcarbonyl)amino]-benzamidetrifluoroacetate. The product was purified by preparative RPHPLC (C18),eluting with a linear gradient from 90/10 through 60/40 (0.01%HCl/acetonitrile) over 180 min.

¹H-NMR; IS-MS, m/e 402.1 (m+1); Analytical HPLC, RT=24.32 min(90/10-60/40, 40 min).

EXAMPLE 108 Preparation ofN-(5-Chloropyridin-2-yl)-2-[(4-isopropylpiperazin-1-ylcarbonyl)amino]-5-trifluoromethylbenzamideHydrochloride

A. 2-(4-boc-Piperazin-1-ylcarbonyl)amino-5-(trifluoromethyl)bromobenzene

By methods substantially equivalent to those described in example 51-A,2-(4-Boc-piperazin-1-ylcarbonyl)amino-5-(trifluoromethyl)bromobenzene(6.4 g, 93%) was prepared from 2-bromo-4-(trifluromethyl)aniline

¹H-NMR; IS-MS, m/e 452.2 (m−); Analysis for C₁₇H₂₁N₃O₃BrF₃: Calcd: C,45.15; H, 4.68; N, 9.29; Found: C, 45.01; H, 4.40; N, 9.15.

B. 2-(4-boc-Piperazin-1-ylcarbonyl)amino-5-trifluoromethylbenzoic Acid

By methods substantially equivalent to those described in example 51-B,2-(4-Boc-piperazin-1-ylcarbonyl)amino-5-trifluoromethylbenzoic acid(2.58 g, 70%) was prepared from2-(4-Boc-piperazin-1-ylcarbonyl)amino-5-(trifluoromethyl)bromobenzene

¹H-NMR; IS-MS, m/e 416.2 (m−).

C. 2-(4-boc-Piperazin-1-yl)-6-trifluoromethyl-4H-3,1-benzoxazin-4-one

By methods substantially equivalent to those described in example 51-C,2-(4-Boc-piperazin-1-yl)-6-trifluoromethyl-4H-3,1-benzoxazin-4-one (1.75g, 71%) was prepared from2-(4-Boc-piperazin-1-ylcarbonyl)amino-5-trifluoromethylbenzoic acid.

¹H-NMR; FD-MS, m/e 399.2 (m).

D.2-[(4-boc-Piperazin-1-ylcarbonyl)amino]-N-(5-chloropyridin-2-yl)-5-trifluoromethylbenzamide

By methods substantially equivalent to those described in example 51-D,2-[(4-Boc-piperazin-1-ylcarbonyl)amino]-N-(5-chloropyridin-2-yl)-5-trifluoromethylbenzamide(0.71 g, 60%) was prepared from2-(4-Boc-piperazin-1-yl)-6-trifluoromethyl-4H-3,1-benzoxazin-4-one

¹H-NMR; IS-MS, m/e 528.1 (m+1).

E.N-(5-Chloropyridin-2-yl)-2-[(piperazin-1-ylcarbonyl)amino]-5-trifluoromethylbenzamideTrifluoroacetate

By methods substantially equivalent to those described in example 9-B,N-(5-chloropyridin-2-yl)-2-[(piperazin-1-ylcarbonyl)amino]-5-trifluoromethylbenzamidetrifluoroacetate (0.525 g, 85%) was prepared from2-[(4-Boc-piperazin-1-yl-carbonyl)amino]-N-(5-chloropyridin-2-yl)-5-trifluoromethylbenzamide

¹H-NMR; IS-MS, m/e 428.1 (m+1).

F.N-(5-Chloropyridin-2-yl)-2-[(4-isopropylpiperazin-1-ylcarbonyl)amino]-5-trifluoromethylbenzamideHydrochloride

By methods substantially equivalent to those described in example 27,N-(5-chloropyridin-2-yl)-2-[(4-isopropylpiperazin-1-ylcarbonyl)amino]-5-trifluoromethylbenzamidehydrochloride (0.37 g, 86%, 99% pure by analytical HPLC) was preparedfromN-(5-chloropyridin-2-yl)-2-[(piperazin-1-ylcarbonyl)amino]-5-trifluoromethylbenzamidetrifluoroacetate.

¹H-NMR; IS-MS, m/e 470.2 (m+1); Analytical HPLC, RT=21.59 min(80/20-40/60, 40 min).

EXAMPLE 109 Preparation ofN-(5-Chloropyridin-2-yl)-2-[(4-isopropylpiperazin-1-ylcarbonyl)amino]-5-trifluoromethoxybenzamideHydrochloride

A.2-(4-boc-Piperazin-1-ylcarbonyl)amino-5-(trifluoromethoxy)bromobenzene

By methods substantially equivalent to those described in example 51-A,2-(4-Boc-piperazin-1-ylcarbonyl)amino-5-(trifluoromethoxy)bromobenzene(7.1 g, 56%) was prepared from 2-bromo-4-(trifluoromethoxy)aniline

¹H-NMR; IS-MS, m/e 466.1 (m−).

B. 2-(1-boc-Piperazin-4-ylcarbonyl)amino-5-trifluoromethoxybenzoic Acid

By methods substantially equivalent to those described in example 51-B,2-(4-Boc-piperazin-1-ylcarbonyl)amino-5-trifluoromethoxybenzoic acid(3.7 g, 100%) was prepared from2-(4-Boc-piperazin-1-ylcarbonyl)amino-5-(trifluoromethoxy)bromobenzene

¹H-NMR; IS-MS, m/e 433.3 (m−).

C. 2-(4-boc-Piperazin-1-yl)-6-trifluoromethoxy-4H-3,1-benzoxazin-4-one

By methods substantially equivalent to those described in example 51-C,2-(4-Boc-piperazin-1-yl)-6-trifluoromethoxy-4H-3,1-benzoxazin-4-one(1.91 g, 56%) was prepared from2-(4-Boc-piperazin-1-ylcarbonyl)amino-5-trifluoromethoxybenzoic acid.

¹H-NMR; IS-MS, m/e 416 (m); Analysis for C₁₈H₂₀N₃O₅F₃: Calcd: C, 52.05;H, 4.85; N, 10.12; Found: C, 52.34; H, 4.82; N, 10.51.

D.2-(4-boc-Piperazin-1-ylcarbonyl)amino]-N-(5-chloropyridin-2-yl)-5-trifluoromethoxybenzamide

By methods substantially equivalent to those described in example 51-D,2-[(4-Boc-piperazin-1-ylcarbonyl)amino]-N-(5-chloropyridin-2-yl)-5-trifluoromethoxybenzamide(0.78 g 74%) was prepared from2-(4-Boc-piperazin-1-yl)-6-trifluoromethoxy-4H-3,1-benzoxazin-4-one

¹H-NMR; IS-MS, m/e 544.3 (m+1).

E.N-(5-Chloropyridin-2-yl)-2-(piperazin-4-ylcarbonyl)amino]-5-trifluoromethoxybenzamideTrifluoroacetate

By methods substantially equivalent to those described in example 9-B,N-(5-chloropyridin-2-yl)-2-[(piperazin-4-ylcarbonyl)amino]-5-trifluoromethoxybenzamidetrifluoroacetate (0.67 g, 93%) was prepared from2-[(4-Boc-piperazin-1-ylcarbonyl)amino]-N-(5-chloropyridin-2-yl)-5-trifluoromethoxybenzamide

¹H-NMR; IS-MS, m/e 444.1 (m+1).

F.N-(5-Chloropyridin-2-yl)-2-[(4-isopropylpiperazin-1-ylcarbonyl)amino]-5-trifluoromethoxybenzamideHydrochloride

By methods substantially equivalent to those described in example 27,N-(5-chloropyridin-2-yl)-2-[(4-isopropylpiperazin-1-ylcarbonyl)amino]-5-trifluoromethoxybenzamidehydrochloride (0.347 g, 62%) was prepared fromN-(5-chloropyridin-2-yl)-2-[(piperazin-4-ylcarbonyl)amino]-5-trifluoromethoxybenzamidetrifluoroacetate.

¹H-NMR; IS-MS, m/e 486.5 (m+1); Analysis forC₂₁H₂₃N₅O₃ClF₃.1.0HCl.0.5H₂O: Calcd: C, 47.47; H, 4.74; N, 13.18; Found:C, 47.28; H, 4.66; N, 12.90.

EXAMPLE 110 Preparation of5-Chloro-N-(5-fluoropyridin-2-yl)-2-[(4-isopropylpiperazin-1-ylcarbonyl)amino]benzamideHydrochloride

A.2-[(4-boc-Piperazin-1-ylcarbonyl)amino]-5-chloro-N-(5-fluoropyridin-2-yl)benzamide

By methods substantially equivalent to those described in example 51-D,2-[(4-Boc-piperazin-1-ylcarbonyl)amino]-5-chloro-N-(5-fluoropyridin-2-yl)benzamide(0.75 g, 71%) was prepared from6-chloro-2-[4-Boc-piperazin-1-yl]-4H-3,1-benzoxazin-4-one and2-amino-5-fluoropyridine

¹H-NMR; IS-MS, m/e 478.2 (m+1); Analysis for C₂₂H₂₅N₅O₄ClF: Calcd: C,55.29; H, 5.27; N, 14.65; Found: C, 55.58; H, 5.32; N, 14.81.

B.5-Chloro-N-(5-fluoropyridin-2-yl)-2-[(piperazin-1-ylcarbonyl)amino]benzamideTrifluoroacetate

By methods substantially equivalent to those described in example 9-B,5-chloro-N-(5-fluoropyridin-2-yl)-2-[(piperazin-1-ylcarbonyl)amino]benzamidetrifluoroacetate (0.619 g, 93%) was prepared from2-[(4-Boc-piperazin-1-ylcarbonyl)amino]-5-chloro-N-(5-fluoropyridin-2-yl)benzamide

¹H-NMR; IS-MS, m/e 378.4 (m+1); Analysis for C₁₇H₁₇N₅O₂ClF.CF₃COOH:Calcd: C, 46.40; H, 3.69; N, 14.24; F, 15.45; Found: C, 46.01; H, 3.67;N, 14.03; F, 15.40.

C.5-Chloro-N-(5-fluoropyridin-2-yl)-2-[(4-isopropylpiperazin-1-ylcarbonyl)amino]benzamideHydrochloride

By methods substantially equivalent to those described in example 27,5-chloro-N-(5-fluoropyridin-2-yl)-2-[(4-isopropylpiperazin-1-ylcarbonyl)amino]benzamidehydrochloride (0.310 g, 68%) was prepared from5-chloro-N-(5-fluoropyridin-2-yl)-2-[(piperazin-1-ylcarbonyl)amino]-benzamidetrifluoroacetate.

¹H-NMR; IS-MS, m/e 420.2 (m+1); Analysis forC₂₀H₂₃N₅O₂ClF.1.5HCl.0.2H₂O: Calcd: C, 50.23; H, 5.25; N, 14.65; Cl,18.54; Found: C, 50.07; H, 4.97; N, 14.44; Cl, 18.81.

EXAMPLE 111 Preparation of5-Chloro-2-[(4-isopropylpiperazin-1-ylcarbonyl)amino]-N-(5-methylpyridin-2-yl)benzamideHydrochloride

A.2-[(4-boc-Piperazin-1-ylcarbonyl)amino]-5-chloro-N-(5-methylpyridin-2-yl)benzamide

By methods substantially equivalent to those described in example 51-D,2-[(4-Boc-piperazin-1-ylcarbonyl)amino]-5-chloro-N-(5-methylpyridin-2-yl)benzamide(0.667 g, 74%) was prepared from2-[4-Boc-piperazin-1-yl]-6-chloro-4H-3,1-benzoxazin-4-one and2-amino-5-methylpyridine

¹H-NMR; IS-MS, m/e 474.1 (m+1); Analysis for C₂₃H₂₈N₅O₄Cl: Calcd: C,58.29; H, 5.95; N, 14.78; Found: C, 58.42; H, 6.15; N, 14.57.

B.5-Chloro-N-(5-methylpyridin-2-yl)-2-[(piperazin-1-ylcarbonyl)amino]benzamideTrifluoroacetate

By methods substantially equivalent to those described in example 9-B,5-chloro-N-(5-methylpyridin-2-yl)-2-[(piperazin-1-ylcarbonyl)amino]benzamidetrifluoroacetate (4.07 g, 99%) was prepared from2-[(4-Boc-piperazin-1-ylcarbonyl)amino]-5-chloro-N-(5-methylpyridin-2-yl)benzamide

¹H-NMR; IS-MS, m/e 374.1 (m+1); Analysis for C₁₈H₂₀N₅O₂Cl.2.1TFA: Calcd:C, 43.48; H, 3.63; N, 11.42; F, 19.52; Found: C, 43.49; H, 3.61; N,11.40; F, 19.98.

C.5-Chloro-2-[(4-isopropylpiperazin-1-ylcarbonyl)amino]-N-(5-methylpyridin-2-yl)benzamideHydrochloride

By methods substantially equivalent to those described in example 27,5-chloro-2-[(4-isopropylpiperazin-1-ylcarbonyl)amino]-N-(5-methylpyridin-2-yl)benzamidehydrochloride (0.263 g, 71%) was prepared from5-chloro-N-(5-methylpyridin-2-yl)-2-[(piperazin-1-ylcarbonyl)amino]-benzamidetrifluoroacetate. The product was purified by reverse phase HPLC,eluting with a gradient from 5% through 35% acetonitrile in 0.05% aq HClover 200 min.

¹H-NMR; IS-MS, m/e 416.3 (m+1); Analysis for C₂₁H₂₆N₅O₂Cl.2.1HCl.0.3H₂O:Calcd: C, 50.66; H, 5.81; N, 14.07; Cl, 22.08; Found: C, 50.69; H, 5.58;N, 14.08; Cl, 22.03.

EXAMPLE 112 Preparation of5-Chloro-N-(5-chloropyridin-2-yl)-2-[1-(4-thianyl)piperidin-4-ylmethylamino]benzamide

A solution of5-chloro-N-(5-chloropyridin-2-yl)-2-(piperidin-4-ylmethylamino)benzamide(0.44 g, 1.2 mmol) in methanol-acetic acid (95:5) (10 mL) was treatedwith tetrahydrothiopyran-4-one (1.34 g, 11.5 mmol) and sodiumcyanoborohydride (4.6 mL of a 1 M solution in tetrahydrofuran). Thereaction mixture was stirred at room temperature for 48 h, then heatedat 50° C. for an additional 60 h. After cooling to room temperature, thesolvent was removed in vacuo; the resulting residue was redissolved inmethanol and directly applied to 5×10 g SCX columns, washed withmethanol and eluted with dichloromethane-2 N ammonia in methanol (1:1).The product fractions were concentrated in vacuo and the residue waspurified via silica gel chromatography. Elution with ethyl acetatefollowed by ethyl acetate-methanol (9:1) afforded the title compound(0.46 g, 84%) as a yellow solid, which was further purified viatrituration in acetonitrile followed by separation of the yellow motherliquor.

¹H-NMR; mp 200.2-202.9° C.; FD-MS, m/e 479.2 (m); Analysis forC₂₃H₂₈N₄OSCl₂: Calcd: C, 57.62; H, 5.89; N, 11.69; Found: C, 57.39; H,6.05; N, 11.51.

EXAMPLE 113 Preparation of5-Chloro-N-(5-chloropyridin-2-yl)-2-[1-(1-ethylpropyl)piperidin-4-ylmethylamino]benzamide

Using the procedure described in example 112,5-chloro-N-(5-chloropyridin-2-yl)-2-(piperidin-4-ylmethylamino)benzamide(0.59 g, 1.5 mmol) was converted to the title compound (0.5 g, 72%). Thematerial was further purified via trituration in acetonitrile followedby separation of the yellow mother liquor.

¹H-NMR; mp 135.7-138.3° C.; FD-MS, m/e 449.2 (m); Analysis forC₂₃H₃₀N₄OCl₂.0.095H₂O: Calcd: C, 61.23; H, 6.75; N, 12.42; Found: C,60.83; H, 6.34; N, 12.31.

EXAMPLE 114 Preparation of5-Chloro-N-(5-chloropyridin-2-yl)-2-(1-isobutylpiperidin-4-ylmethylamino)benzamide

Using the procedure described in example 1125-chloro-N-(5-chloropyridin-2-yl)-2-(piperidin-4-ylmethylamino)benzamide(0.42 g, 1.1 mmol) was converted to the title compound (0.4 g, 85%). Thematerial was further purified via trituration in acetonitrile followedby separation of the yellow mother liquor.

¹H-NMR; mp 121.3-122.2° C.; FD-MS, m/e 435.2 (m); Analysis forC₂₂H₂₈N₄OCl₂: Calcd: C, 60.69; H, 6.48; N, 12.87; Found: C, 60.39; H,6.39; N, 12.68.

EXAMPLE 115 Preparation ofN-(5-Chloropyridin-2-yl)-2-[[1-(4-hydroxybenzyl)piperidin-4-ylmethyl]amino]benzamide

N-(5-Chloropyridin-2-yl)-2-(piperidin-4-ylmethylamino)benzamide (0.034g, 0.1 mmol) was converted to the title compound (0.0430 g, 94%) usingthe procedure described in example 78. The product was obtained as anoily residue which was triturated in diethyl ether to afford a solidwhich was identified by LC-MS (Method A).

LC-MS: 91% pure, R_(t)=2.750 min, m/e 451.2 (m).

EXAMPLE 116 Preparation ofN-(5-Chloropyridin-2-yl)-2-[1-(3-thiophenylmethyl)piperidin-4-ylmethyl]amino]benzamide

N-(5-Chloropyridin-2-yl)-2-(piperidin-4-ylmethylamino)benzamide (0.034g, 0.1 mmol) was converted to the title compound (0.042 g, 95%) usingthe procedure described in example 78. The product was obtained as anoily residue which was further purified on silica gel. Elution withethyl acetate-2 N ammonia in methanol (95:5) followed by triturationwith diethyl ether-acetonitrile afforded a solid which was identified byLC-MS (Method A).

LC-MS: 89% pure, R_(t)=3.421 min, m/e 441.1 (m).

EXAMPLE 117 Preparation ofN-(5-Chloropyridin-2-yl)-2-[[1-(2-pyridinylmethyl)piperidin-4-ylmethyl]amino]benzamide

N-(5-Chloropyridin-2-yl)-2-(piperidin-4-ylmethylamino)benzamide (0.114g, 0.33 mmol) was converted to the title compound (0.093 g, 65%) usingthe procedure described in example 78. The product was obtained as anoily residue which was further purified on silica gel. Elution withethyl acetate-2 N ammonia in methanol (95:5) followed by triturationwith acetonitrile afforded a solid which was identified by LC-MS (MethodA).

LC-MS: 97% pure, R_(t)=2.631 min, m/e 436.2 (m).

EXAMPLE 118 Preparation ofN-(5-Chloropyridin-2-yl)-2-[[1-(2-methylbenzyl)piperidin-4-ylmethyl]amino]benzamide

N-(5-Chloropyridin-2-yl)-2-(piperidin-4-ylmethylamino)benzamide (0.034g, 0.1 mmol) was converted to the title compound (0.017 g, 38%) usingthe procedure described in example 78. The product was obtained as anoily residue which was triturated in diethyl ether-acetonitrile. Theresulting solid was identified as the title compound by LC-MS (MethodA).

LC-MS: 69% pure, R_(t)=4.204 min, m/e 449.2 (m).

EXAMPLE 119 Preparation ofN-(5-Chloropyridin-2-yl)-2-[[1-(2-methoxybenzyl)piperidin-4-ylmethyl]amino]benzamide

N-(5-Chloropyridin-2-yl)-2-(piperidin-4-ylmethylamino)benzamide (0.034g, 0.1 mmol) was converted to the title compound (0.041 g, 88%) usingthe procedure described in example 78. The product was obtained as anoily residue which was triturated in diethyl ether-acetonitrile toprovide a solid which was identified as the title compound by LC-MS(Method A).

LC-MS: 95% pure, R_(t)=4.278 min, m/e 465.2 (m).

EXAMPLE 120 Preparation ofN-(5-Chloropyridin-2-yl)-2-[[1-(4-methoxybenzyl)piperidin-4-ylmethyl]amino]benzamide

N-(5-Chloropyridin-2-yl)-2-(piperidin-4-ylmethylamino)benzamide (0.034g, 0.1 mmol) was converted to the title compound (0.044 g, 94%) usingthe procedure described in example 78. The product was obtained as anoily residue which was triturated in diethyl ether-acetonitrile toprovide a solid which was identified as the title compound by LC-MS(Method A).

LC-MS: 91% pure, R_(t)=3.938 min, m/e 465.2 (m).

EXAMPLE 121 Preparation ofN-(5-Chloropyridin-2-yl)-2-[[1-(3-hydroxybenzyl)piperidin-4-ylmethyl]amino]benzamide

N-(5-Chloropyridin-2-yl)-2-(piperidin-4-ylmethylamino)benzamide (0.034g, 0.1 mmol) was converted to the title compound (0.043 g, 95%) usingthe procedure described in example 78. The product was obtained as anoily residue which was triturated in diethyl ether-acetonitrile toprovide a solid which was identified as the title compound by LC-MS(Method A).

LC-MS: 91% pure, R_(t)=2.839 min, m/e 451.1 (m).

EXAMPLE 122 Preparation ofN-(5-Chloropyridin-2-yl)-2-[[1-(2-thiophenylmethyl)piperidin-4-ylmethyl]amino]benzamide

N-(5-Chloropyridin-2-yl)-2-(piperidin-4-ylmethylamino)benzamide (0.034g, 0.1 mmol) was converted to the title compound (0.041 g, 92%) usingthe procedure described in example 78. The product was obtained as anoily residue which was further purified on silica gel. Elution withethyl acetate-2 N ammonia in methanol (95:5) followed by triturationwith diethyl ether afforded a solid which was identified by LC-MS(Method A).

LC-MS: 88% pure, R_(t)=3.377 min, m/e 441.1 (m).

EXAMPLE 123 Preparation ofN-(5-Chloropyridin-2-yl)-2-[[1-(2-chlorobenzyl)piperidin-4-ylmethyl]amino]benzamide

N-(5-Chloropyridin-2-yl)-2-(piperidin-4-ylmethylamino)benzamide (0.034g, 0.1 mmol) was converted to the title compound (0.025 g, 53%) usingthe procedure described in example 78. The product was obtained as anoily residue which was triturated in diethyl ether-acetonitrile toprovide a solid which was identified as the title compound by LC-MS(Method A).

LC-MS: 91% pure, R_(t)=4.175 min, m/e 469.1 (m).

EXAMPLE 124 Preparation ofN-(5-Chloropyridin-2-yl)-2-[[1-(2-fluorobenzyl)piperidin-4-ylmethyl]amino]benzamide

N-(5-Chloropyridin-2-yl)-2-(piperidin-4-ylmethylamino)benzamide (0.034g, 0.1 mmol) was converted to the title compound (0.045 g, 100%) usingthe procedure described in example 78. The product was obtained as anoily residue which was triturated in diethyl ether-acetonitrile toprovide a solid which was identified as the title compound by LC-MS(Method A).

LC-MS: 92% pure, R_(t)=3.752 min, m/e 453.1 (m).

EXAMPLE 125 Preparation ofN-(5-Chloropyridin-2-yl)-2-[[1-(3-fluorobenzyl)piperidin-4-ylmethyl]amino]benzamide

N-(5-Chloropyridin-2-yl)-2-(piperidin-4-ylmethylamino)benzamide (0.034g, 0.1 mmol) was converted to the title compound (0.044 g, 97%) usingthe procedure described in example 78. The product was obtained as anoily residue which was triturated in diethyl ether-acetonitrile toprovide a solid which was identified as the title compound by LC-MS(Method A).

LC-MS: 94% pure, R_(t)=3.831 min, m/e 453.1 (m).

EXAMPLE 126 Preparation ofN-(5-Chloropyridin-2-yl)-2-[(1-benzylpiperidin-4-ylmethyl)amino]benzamide

N-(5-Chloropyridin-2-yl)-2-(piperidin-4-ylmethylamino)benzamide (0.114g, 0.33 mmol) was converted to the title compound (0.144 g, 100%) usingthe procedure described in example 78. The product was obtained as anoily residue which was further purified on silica gel. Elution withethyl acetate-2 N ammonia in methanol (95:5) followed by triturationwith diethyl ether afforded a solid which was identified by LC-MS(Method A).

LC-MS: 97% pure, R_(t)=3.713 min, m/e 435.1 (m).

EXAMPLE 127 Preparation ofN-(5-Chloropyridin-2-yl)-2-[[1-(4-methylbenzyl)piperidin-4-ylmethyl]amino]benzamide

N-(5-Chloropyridin-2-yl)-2-(piperidin-4-ylmethylamino)benzamide (0.034g, 0.1 mmol) was converted to the title compound (0.04 g, 88%) using theprocedure described in example 78. The product was obtained as an oilyresidue which was triturated in diethyl ether-acetonitrile to provide asolid which was identified as the title compound by LC-MS (Method A).

LC-MS: 88% pure, R_(t)=4.388 min, m/e 449.2 (m).

EXAMPLE 128

Preparation ofN-(5-Chloropyridin-2-yl)-2-[[1-(4-chlorobenzyl)piperidin-4-ylmethyl]amino]benzamide

N-(5-Chloropyridin-2-yl)-2-(piperidin-4-ylmethylamino)benzamide (0.034g, 0.1 mmol) was converted to the title compound (0.046 g, 98%) usingthe procedure described in example 78. The product was obtained as anoily residue which was triturated in diethyl ether-acetonitrile toprovide a solid which was identified as the title compound by LC-MS(Method A).

LC-MS: 99% pure, R_(t)=4.407 min, m/e 469.1 (m).

EXAMPLE 129 Preparation ofN-(5-Chloropyridin-2-yl)-2-[[1-(3-methoxybenzyl)piperidin-4-ylmethyl]amino]benzamide

N-(5-Chloropyridin-2-yl)-2-(piperidin-4-ylmethylamino)benzamide (0.034g, 0.1 mmol) was converted to the title compound (0.046 g, 99%) usingthe procedure described in example 78. The product was obtained as anoily residue which was triturated in diethyl ether-acetonitrile toprovide a solid which was identified as the title compound by LC-MS(Method A).

LC-MS: 87% pure, R_(t)=4.003 min, m/e 465.2 (m).

EXAMPLE 130 Preparation ofN-(5-Chloropyridin-2-yl)-2-[[1-(4-bromobenzyl)piperidin-4-ylmethyl]amino]benzamide

N-(5-Chloropyridin-2-yl)-2-(piperidin-4-ylmethylamino)benzamide (0.034g, 0.1 mmol) was converted to the title compound (0.052 g, 100%) usingthe procedure described in example 78. The product was obtained as anoily residue which was triturated in diethyl ether-acetonitrile toprovide a solid which was identified as the title compound by LC-MS(Method A).

LC-MS: 91% pure, R_(t)=4.532 min, m/e 515.1 (m+1).

EXAMPLE 131 Preparation ofN-(5-Chloropyridin-2-yl)-2-[[1-(2-bromobenzyl)piperidin-4-ylmethyl]amino]benzamide

N-(5-Chloropyridin-2-yl)-2-(piperidin-4-ylmethylamino)benzamide (0.034g, 0.1 mmol) was converted to the title compound (0.031 g, 61%) usingthe procedure described in example 78. The product was obtained as anoily residue which was triturated in diethyl ether-acetonitrile toprovide a solid which was identified as the title compound by LC-MS(Method A).

LC-MS: 86% pure, R_(t)=4.335 min, m/e 515.1 (m+1).

EXAMPLE 132 Preparation ofN-(5-Chloropyridin-2-yl)-2-[[1-(3-methylbenzyl)piperidin-4-ylmethyl]amino]benzamide

N-(5-Chloropyridin-2-yl)-2-(piperidin-4-ylmethylamino)benzamide (0.034g, 0.1 mmol) was converted to the title compound (0.045 g, 100%) usingthe procedure described in example 78. The product was obtained as anoily residue which was triturated in diethyl ether-acetonitrile toprovide a solid which was identified as the title compound by LC-MS(Method A).

LC-MS: 88% pure, R_(t)=4.326 min, m/e 449.2 (m).

EXAMPLE 133 Preparation ofN-(5-Chloropyridin-2-yl)-2-[1-(cyclohexylmethyl)piperidin-4-ylmethyl)amino]benzamide

N-(5-Chloropyridin-2-yl)-2-(piperidin-4-ylmethylamino)benzamide (0.034g, 0.1 mmol) was converted to the title compound (0.039 g, 88%) usingthe procedure described in example 78. The product was obtained as anoily residue which was triturated in diethyl ether-acetonitrile toprovide a solid which was identified as the title compound by LC-MS(Method A).

LC-MS: 89% pure, R_(t)=4.535 min, m/e 441.2 (m).

EXAMPLE 134 Preparation ofN-(5-Chloropyridin-2-yl)-2-[[1-(3-furanylmethyl)piperidin-4-ylmethyl]amino]benzamide

N-(5-Chloropyridin-2-yl)-2-(piperidin-4-ylmethylamino)benzamide (0.034g, 0.1 mmol) was converted to the title compound (0.039 g, 92%) usingthe procedure described in example 78. The product was obtained as anoily residue which was was further purified on silica gel. Elution withethyl acetate afforded an oily material which was identified by LC-MS(Method A).

LC-MS: 90% pure, R_(t)=3.082 min, m/e 425.2 (m).

EXAMPLE 135 Preparation ofN-(5-Chloropyridin-2-yl)-2-[[1-(4-imidazolylmethyl)piperidin-4-ylmethyl]amino]benzamide

N-(5-Chloropyridin-2-yl)-2-(piperidin-4-ylmethylamino)benzamide (0.034g, 0.1 mmol) was converted to the title compound (0.030 g, 71%) usingthe procedure described in example 78. The product was obtained as anoily residue which was was further purified on silica gel. Elution withdichloromethane-methanol (9:1) afforded an oily material which wasidentified by LC-MS (Method A).

LC-MS: 96% pure, R_(t)=1.407 min, m/e 425.1 (m).

EXAMPLE 136 Preparation ofN-(5-Chloropyridin-2-yl)-2-[[1-(2-furanylmethyl)piperidin-4-ylmethyl]amino]benzamide

N-(5-Chloropyridin-2-yl)-2-(piperidin-4-ylmethylamino)benzamide (0.034g, 0.1 mmol) was converted to the title compound (0.032 g, 75%) usingthe procedure described in example 78. The product was obtained as anoily residue which was was further purified on silica gel. Elution withethyl acetate afforded an oily material which was identified by LC-MS(Method A).

LC-MS: 90% pure, R_(t)=3.066 min, m/e 425.1 (m).

EXAMPLE 137 Preparation ofN-(5-Chloropyridin-2-yl)-2-[[1-(3-pyridinylmethyl)piperidin-4-ylmethyl]amino]benzamide

N-(5-Chloropyridin-2-yl)-2-(piperidin-4-ylmethylamino)benzamide (0.034g, 0.1 mmol) was converted to the title compound (0.058 g, 100%) usingthe procedure described in example 78. The product was obtained as anoily residue which was was further purified on silica gel. Elution withdichloromethane-methanol (9:1) afforded an oily material which wasidentified by LC-MS (Method A).

LC-MS: 87% pure, R_(t)=1.632 min, m/e 436.1 (m).

EXAMPLE 138 Preparation ofN-(5-Chloropyridin-2-yl)-2-[[1-(2-imidazolylmethyl)piperidin-4-ylmethyl]amino]benzamide

N-(5-Chloropyridin-2-yl)-2-(piperidin-4-ylmethylamino)benzamide (0.034g, 0.1 mmol) was converted to the title compound (0.029 g, 68%) usingthe procedure described in example 78. The product was obtained as anoily residue which was was further purified on silica gel. Elution withethyl acetate-2 N ammonia in methanol (95:5) followed by triturationwith diethyl ether-acetonitrile afforded a solid which was identified byLC-MS (Method A).

LC-MS: 66% pure, R_(t)=1.481 min, m/e 425.1 (m).

EXAMPLE 139 Preparation ofN-(5-Chloropyridin-2-yl)-2-[[1-[1-(4-methoxyphenyl)ethyl]piperidin-4-ylmethyl]amino]benzamide

Using the procedure described in example 103,N-(5-chloropyridin-2-yl)-2-(piperidin-4-ylmethylamino)benzamide (0.03 g,0.1 mmol) was converted to the title compound (0.027 g, 63%), which wasidentified by LC-MS (Method A).

LC-MS: 95% pure, R_(t)=4.229 min, m/e 479.3 (m).

EXAMPLE 140 Preparation ofN-(5-Chloropyridin-2-yl)-2-[[1-[1-(2-thiophenyl)ethyl]piperidin-4-ylmethyl]amino]benzamide

Using the procedure described in example 103,N-(5-chloropyridin-2-yl)-2-(piperidin-4-ylmethylamino)benzamide (0.03 g,0.1 mmol) was converted to the title compound (0.039 g, 95%), which wasidentified by LC-MS (Method A).

LC-MS: 91% pure, R_(t)=3.868 min, m/e 455.2 (m).

EXAMPLE 141 Preparation ofN-(5-Chloropyridin-2-yl)-2-[[1-[1-(4-bromophenyl)ethyl]piperidin-4-ylmethyl]amino]benzamide

Using the procedure described in example 103,N-(5-chloropyridin-2-yl)-2-(piperidin-4-ylmethylamino)benzamide (0.03 g,0.1 mmol) was converted to the title compound (0.041 g, 86%), which wasidentified by LC-MS (Method A).

LC-MS: 97% pure, R_(t)=4.878 min, m/e 529.2 (m+1).

EXAMPLE 142 Preparation ofN-(5-Chloropyridin-2-yl)-2-[[1-[1-(4-chlorophenyl)ethyl]piperidin-4-ylmethyl]amino]benzamide

Using the procedure described in example 103,N-(5-chloropyridin-2-yl)-2-(piperidin-4-ylmethylamino)benzamide (0.03 g,0.1 mmol) was converted to the title compound (0.043 g, 99%), which wasidentified by LC-MS (Method A).

LC-MS: 92% pure, R_(t)=5.001 min, m/e 483.2 (m).

EXAMPLE 143 Preparation ofN-(5-Chloropyridin-2-yl)-2-[[1-[1-(2,5-dimethylfuran-3-yl)ethyl]piperidin-4-ylmethyl]amino]benzamide

Using the procedure described in example 103,N-(5-chloropyridin-2-yl)-2-(piperidin-4-ylmethylamino)benzamide (0.03 g,0.1 mmol) was converted to the title compound (0.030 g, 71%), which wasidentified by LC-MS (Method A).

LC-MS: 96% pure, R_(t)=4.624 min, m/e 467.3 (m).

EXAMPLE 144 Preparation ofN-(5-Chloropyridin-2-yl)-2-[[1-[1-(3-chlorophenyl)ethyl]piperidin-4-ylmethyl]amino]benzamide

Using the procedure described in example 103,N-(5-chloropyridin-2-yl)-2-(piperidin-4-ylmethylamino)benzamide (0.03 g,0.1 mmol) was converted to the title compound (0.026 g, 60%), which wasidentified by LC-MS (Method B).

LC-MS: 99% pure, R_(t)=7.883 min, m/e 483.2 (m).

EXAMPLE 145 Preparation ofN-(5-Chloropyridin-2-yl)-2-[[1-(1-methylpropyl)piperidin-4-ylmethyl]amino]benzamide

Using the procedure described in example 103,N-(5-chloropyridin-2-yl)-2-(piperidin-4-ylmethylamino)benzamide (0.03 g,0.1 mmol) was converted to the title compound (0.034 g, 94%), which wasidentified by LC-MS (Method A).

LC-MS: 85% pure, R_(t)=3.060 min, m/e 401.3 (m).

EXAMPLE 146 Preparation ofN-(5-Chloropyridin-2-yl)-2-[[1-(1-ethylpropyl)piperidin-4-ylmethyl]amino]benzamide

Using the procedure described in example 103,N-(5-chloropyridin-2-yl)-2-(piperidin-4-ylmethylamino)benzamide (0.03 g,0.1 mmol) was converted to the title compound (0.035 g, 94%), which wasidentified by LC-MS (Method A).

LC-MS: 92% pure, R_(t)=3.440 min, m/e 415.3 (m).

EXAMPLE 147 Preparation ofN-(5-Chloropyridin-2-yl)-2-[[1-(4-thianyl)piperidin-4-ylmethyl]amino]benzamide

Using the procedure described in example 103,N-(5-chloropyridin-2-yl)-2-(piperidin-4-ylmethylamino)benzamide (0.03 g,0.1 mmol) was converted to the title compound (0.039 g, 97%), which wasidentified by LC-MS (Method A).

LC-MS: 99% pure, R_(t)=3.063 min, m/e 445.5 (m).

EXAMPLE 148 Preparation ofN-(5-Chloropyridin-2-yl)-2-[[1-(1-cyclopropylethyl)piperidin-4-ylmethyl]amino]benzamide

Using the procedure described in example 103,N-(5-chloropyridin-2-yl)-2-(piperidin-4-ylmethylamino)benzamide (0.03 g,0.1 mmol) was converted to the title compound (0.032 g, 86%), which wasidentified by LC-MS (Method A).

LC-MS: 91% pure, R_(t)=3.276 min, m/e 413.3 (m).

EXAMPLE 149 Preparation ofN-(5-Chloropyridin-2-yl)-2-[(1-cyclohexylpiperidin-4-ylmethyl)amino]benzamide

Using the procedure described in example 103,N-(5-chloropyridin-2-yl)-2-(piperidin-4-ylmethylamino)benzamide (0.03 g,0.1 mmol) was converted to the title compound, which was identified byLC-MS (Method A). Further purification on silica gel provided cleanmaterial (0.015 g, 39%) 96% pure by HPLC.

LC-MS: R_(t)=3.598 min, m/e 427.3 (m).

EXAMPLE 150 Preparation ofN-(5-Chloropyridin-2-yl)-2-[[1-(4-tetrahydropyran-4-yl)piperidin-4-ylmethyl]amino]benzamide

Using the procedure described in example 103,N-(5-chloropyridin-2-yl)-2-(piperidin-4-ylmethylamino)benzamide (0.03 g,0.1 mmol) was converted to the title compound, which was identified byLC-MS (Method A). Further purification on silica gel provided cleanmaterial (0.022 g, 57%) 87% pure by HPLC.

LC-MS: R_(t)=2.150 min, m/e 429.3 (m).

EXAMPLE 151 Preparation ofN-(5-Chloropyridin-2-yl)-2-[[1-(3-thiolanyl)piperidin-4-ylmethyl]amino]benzamide

Using the procedure described in example 103,N-(5-chloropyridin-2-yl)-2-(piperidin-4-ylmethylamino)benzamide (0.03 g,0.1 mmol) was converted to the title compound, which was identified byLC-MS (Method A). Further purification on silica gel provided cleanmaterial (0.012 g, 31%) 90% pure by HPLC.

LC-MS: R_(t)=2.625 min, m/e 431.2 (m).

EXAMPLE 152 Preparation ofN-(5-Chloropyridin-2-yl)-2-[(1-cyclopentylpiperidin-4-ylmethyl)amino]benzamide

Using the procedure described in example 103,N-(5-chloropyridin-2-yl)-2-(piperidin-4-ylmethylamino)benzamide (0.03 g,0.1 mmol) was converted to the title compound (0.031 g, 83%), which wasidentified by LC-MS (Method A).

LC-MS: 87% pure, R_(t)=3.141 min, m/e 413.3 (m).

EXAMPLE 153 Preparation ofN-(5-Chloropyridin-2-yl)-2-[[1-[1-(2-pyridyl)ethyl]piperidin-4-ylmethyl]amino]benzamide

Using the procedure described in example 103,N-(5-chloropyridin-2-yl)-2-(piperidin-4-ylmethylamino)benzamide (0.03 g,0.1 mmol) was converted to the title compound (0.035 g, 86%), which wasidentified by LC-MS (Method A).

LC-MS: 88% pure, R_(t)=2.934 min, m/e 450.3 (m).

EXAMPLE 154 Preparation ofN-(5-Chloropyridin-2-yl)-2-[(1-cyclobutylpiperidin-4-ylmethyl)amino]benzamide

Using the procedure described in example 103,N-(5-chloropyridin-2-yl)-2-(piperidin-4-ylmethylamino)benzamide (0.03 g,0.1 mmol) was converted to the title compound (0.034 g, 95%), which wasidentified by LC-MS (Method A).

LC-MS: 51% pure, R_(t)=2.793 min, m/e 399.2 (m).

EXAMPLE 155 Preparation ofN-(5-Chloropyridin-2-yl)-2-[[1-(1-propylbutyl)piperidin-4-ylmethyl]amino]benzamide

Using the procedure described in example 103,N-(5-chloropyridin-2-yl)-2-(piperidin-4-ylmethylamino)benzamide (0.03 g,0.1 mmol) was converted to the title compound (0.026 g, 65%), which wasidentified by LC-MS (Method A).

LC-MS: 98% pure, R_(t)=4.759 min, m/e 443.3 (m).

EXAMPLE 156 Preparation ofN-(5-Chloropyridin-2-yl)-2-[[1-(2-indanyl)piperidin-4-ylmethyl]amino]benzamide

Using the procedure described in example 103,N-(5-chloropyridin-2-yl)-2-(piperidin-4-ylmethylamino)benzamide (0.03 g,0.1 mmol) was converted to the title compound (0.027 g, 65%), which wasidentified by LC-MS (Method A).

LC-MS: ca. 85% pure, R_(t)=4.197 min, m/e 461.3 (m).

EXAMPLE 157 Preparation ofN-(5-Chloropyridin-2-yl)-2-[[1-[1-(2-thiazolyl)ethyl]piperidin-4-ylmethyl)amino]benzamide

Using the procedure described in example 103,N-(5-chloropyridin-2-yl)-2-(piperidin-4-ylmethylamino)benzamide (0.03 g,0.1 mmol) was converted to the title compound (0.020 g, 49%), which wasidentified by LC-MS (Method A).

LC-MS: 100% pure, R_(t)=2.785 min, m/e 456.2 (m).

EXAMPLE 158 Preparation ofN-(5-Chloropyridin-2-yl)-2-[[1-[1-(3-pyridinyl)ethyl]piperidin-4-ylmethyl]amino]benzamide

Using the procedure described in example 103,N-(5-chloropyridin-2-yl)-2-(piperidin-4-ylmethylamino)benzamide (0.03 g,0.1 mmol) was converted to the title compound, which was purified onsilica gel to afford clean material (0.024 g, 59%) 98% pure by HPLC.FD-MS, m/e 450.2 (m).

EXAMPLE 159 Preparation ofN-(5-Chloropyridin-2-yl)-2-[[1-[1-(2-furanyl)ethyl]piperidin-4-ylmethyl]amino]benzamide

Using the procedure described in example 103,N-(5-chloropyridin-2-yl)-2-(piperidin-4-ylmethylamino)benzamide (0.03 g,0.1 mmol) was converted to the title compound (0.022 g, 56%), which wasidentified by LC-MS (Method A).

LC-MS: 90% pure, R_(t)=3.442 min, m/e 439.2 (m).

EXAMPLE 160 Preparation ofN-(5-Chloropyridin-2-yl)-2-[[1-[1-(3-fluorophenyl)ethyl]piperidin-4-ylmethyl]amino]benzamide

Using the procedure described in example 103,N-(5-chloropyridin-2-yl)-2-(piperidin-4-ylmethylamino)benzamide (0.03 g,0.1 mmol) was converted to the title compound (0.036 g, 86%), which wasidentified by LC-MS (Method A).

LC-MS: ca. 90% pure, R_(t)=4.193 min, m/e 467.3 (m).

EXAMPLE 161 Preparation ofN-(5-Chloropyridin-2-yl)-2-[[1-[1-(4-fluorophenyl)ethyl]piperidin-4-ylmethyl)amino]benzamide

Using the procedure described in example 103,N-(5-chloropyridin-2-yl)-2-(piperidin-4-ylmethylamino)benzamide (0.03 g,0.1 mmol) was converted to the title compound (0.036 g, 86%), which wasidentified by LC-MS (Method A).

LC-MS: 92% pure, R_(t)=4.185 min, m/e 467.3 (m).

EXAMPLE 162 Preparation ofN-(5-Chloropyridin-2-yl)-2-[[1-[1-(2-methoxyphenyl)ethyl]piperidin-4-ylmethyl]amino]benzamide

Using the procedure described in example 103,N-(5-chloropyridin-2-yl)-2-(piperidin-4-ylmethylamino)benzamide (0.03 g,0.1 mmol) was converted to the title compound (0.040 g, 93%), which wasidentified by LC-MS (Method A).

LC-MS: 100% pure, R_(t)=4.588 min, m/e 479.3 (m).

EXAMPLE 163 Preparation ofN-(5-Chloropyridin-2-yl)-2-[[1-[1-(4-methylphenyl)ethyl]piperidin-4-ylmethyl]amino]benzamide

Using the procedure described in example 103,N-(5-chloropyridin-2-yl)-2-(piperidin-4-ylmethylamino)benzamide (0.03 g,0.1 mmol) was converted to the title compound (0.036 g, 86%), which wasidentified by LC-MS (Method A).

LC-MS: ca. 95% pure, R_(t)=4.656 min, m/e 463.3 (m).

EXAMPLE 164 Preparation ofN-(5-Chloropyridin-2-yl)-2-[[1-[1-(3-methoxyphenyl)ethyl]piperidin-4-ylmethyl]amino]benzamide

Using the procedure described in example 103,N-(5-chloropyridin-2-yl)-2-(piperidin-4-ylmethylamino)benzamide (0.03 g,0.1 mmol) was converted to the title compound (0.039 g, 90%), which wasidentified by LC-MS (Method A).

LC-MS: 96% pure, R_(t)=4.296 min, m/e 479.3 (m).

EXAMPLE 165 Preparation ofN-(5-Chloropyridin-2-yl)-2-[[1-[1-(3-hydroxyphenyl)ethyl]piperidin-4-ylmethyl]amino]benzamide

Using the procedure described in example 103,N-(5-chloropyridin-2-yl)-2-(piperidin-4-ylmethylamino)benzamide (0.03 g,0.1 mmol) was converted to the title compound (0.031 g, 74%), which wasidentified by LC-MS (Method A).

LC-MS: ca. 100% pure, R_(t)=3.016 min, m/e 465.3 (m).

EXAMPLE 166 Preparation ofN-(5-Chloropyridin-2-yl)-2-[[1-[1-(2-hydroxyphenyl)ethyl]piperidin-4-ylmethyl]amino]benzamide

Using the procedure described in example 103,N-(5-chloropyridin-2-yl)-2-(piperidin-4-ylmethylamino)benzamide (0.03 g,0.1 mmol) was converted to the title compound (0.020 g, 48%), which wasidentified by LC-MS (Method A).

LC-MS: 100% pure, R_(t)=3.830 min, m/e 465.3 (m).

EXAMPLE 167 Preparation ofN-(5-Chloropyridin-2-yl)-2-[[1-[1-(2-methylphenyl)ethyl]piperidin-4-ylmethyl]amino]benzamide

Using the procedure described in example 103,N-(5-chloropyridin-2-yl)-2-(piperidin-4-ylmethylamino)benzamide (0.03 g,0.1 mmol) was converted to the title compound (0.025 g, 60%), which wasidentified by LC-MS (Method A).

LC-MS: 94% pure, R_(t)=4.463 min, m/e 463.3 (m).

EXAMPLE 168 Preparation ofN-(5-Chloropyridin-2-yl)-2-[[1-(1-phenylethyl)piperidin-4-ylmethyl]amino]benzamide

Using the procedure described in example 103,N-(5-chloropyridin-2-yl)-2-(piperidin-4-ylmethylamino)benzamide (0.03 g,0.1 mmol) was converted to the title compound (0.035 g, 87%), which wasidentified by LC-MS (Method A).

LC-MS: 100% pure, R_(t)=3.828 min, m/e 449.3 (m).

EXAMPLE 169 Preparation ofN-(5-Chloropyridin-2-yl)-2-[[1-[1-(2-fluorophenyl)ethyl]piperidin-4-ylmethyl]amino]benzamide

Using the procedure described in example 103,N-(5-chloropyridin-2-yl)-2-(piperidin-4-ylmethylamino)benzamide (0.03 g,0.1 mmol) was converted to the title compound (0.023 g, 55%), which wasidentified by LC-MS (Method A).

LC-MS: ca. 95% pure, R_(t)=4.114 min, m/e 467.3 (m).

EXAMPLE 170 Preparation ofN-(5-Chloropyridin-2-yl)-2-[[1-[1-(3-methylphenyl)ethyl]piperidin-4-ylmethyl]amino]benzamide

Using the procedure described in example 103,N-(5-chloropyridin-2-yl)-2-(piperidin-4-ylmethylamino)benzamide (0.03 g,0.1 mmol) was converted to the title compound (0.026 g, 62%), which wasidentified by LC-MS (Method A).

LC-MS: ca. 95% pure, R_(t)=4.692 min, m/e 463.3 (m).

EXAMPLE 171 Preparation ofN-(5-Chloropyridin-2-yl)-2-[[1-(1-methylpiperidin-4-yl)piperidin-4-ylmethyl]amino]benzamide

Using the procedure described in example 103,N-(5-chloropyridin-2-yl)-2-(piperidin-4-ylmethylamino)benzamide (0.03 g,0.1 mmol) was converted to the title compound (0.032 g, 80%), which wasidentified by LC-MS (Method A).

LC-MS: 94% pure, R_(t)=1.387 min, m/e 442.3 (m).

EXAMPLE 172 Preparation ofN-(5-Chloropyridin-2-yl)-2-[(1-methylpiperidin-4-ylmethyl)amino]benzamideHydrochloride

To a solution ofN-(5-chloropyridin-2-yl)-2-(piperidin-4-ylmethylamino)benzamide (0.132g, 0.4 mmol) in ethanol (5 mL), 88% formic acid was added (160 μL, 1.9mmol) followed by 36% aqueous formaldeyde (80 μL, 1.9 mmol) The reactionmixture was heated at 80° C. for 16 h; then it was allowed to cool toroom temperature before directly applying it to an SCX column. Afterwashing well with methanol, the product was gravity-eluted with 1 Nammonia in methanol. The product fractions were concentrated in vacuo,giving rise to 0.12 g of an oily residue which corresponded to a 1:2mixture of the title compound to bis-methylated product, as determinedby LC-MS (Method B). The title compound was isolated from the mixture asthe pure HCl salt utilizing preparative HPLC methods.

¹H-NMR; LC-MS: 86% pure, R_(t)=6.120 min, m/e 359.2 (m).

EXAMPLE 173 Preparation ofN-(5-Chloropyridin-2-yl)-2-[(1-isopropylpiperidin-4-ylcarbonyl)amino]-5-methylsulfonylbenzamideHydrochloride

A. 4-(Methylsulfonyl)nitrobenzene

To a stirring solution of methyl 4-nitrophenyl sulfide (10 g, 59.1 mmol)in chloroform at 0° C. was added m-chloroperoxybenzoic acid (55.6 g,177.3 mmol). After 3 h, ethyl acetate (1.2 L) was added followed by satdaq sodium bisulfite. After stirring overnight, the layers were separatedand the organic phase was washed with satd aq sodium bicarbonate (3×200mL), followed by brine, and then dried over MgSO₄, filtered andconcentrated in vacuo to give 11.27 g (95%) of the title compound.

¹H-NMR; FD-MS, m/e 201.1 (m+); Analysis for C₇H₇NO₄S: Calcd: C, 41.79;H, 3.51; N, 6.96; Found: C, 41.79; H, 3.59; N, 6.82.

B. 4-(Methylsulfonyl)aniline

A solution of 4-(methylsulfonyl)nitrobenzene (6.26 g, 31.1 mmol) in THF(200 mL) and ethanol (100 mL) was placed in a high pressure reactionvessel and to this solution was added 5% Pd/C (1.6 g). The vessel wasshaken for 8 h under an atmosphere of hydrogen (60 psi). The solutionwas then filtered through diatomaceous earth, partially concentrated invacuo, and diluted with diethyl ether. The resulting precipitate wasfiltered and dried in vacuo to give 4.84 g (91%) of a tan solid.

¹H-NMR; IS-MS, m/e 172.1 (m+1); Analysis for C₇H₉NO₂S: Calcd: C, 49.11;H, 5.30; N, 8.18; Found: C, 49.28; H, 5.48; N, 7.91.

C. 2-Iodo-4-(methylsulfonyl)aniline

To a solution of iodine (20.8 g, 81.8 mmol) and silver sulfate (25.5 g,81.8 mmol) in ethanol (1 L) was added 4-(methylsulfonyl)aniline (14 g,81.8 mmol). After stirring overnight, the solution was filtered. Theprecipitate was then suspended in THF and stirred for 48 h, thenfiltered again and the filtrate was concentrated in vacuo to give 15.5 g(64%) of tan solid. The original filtrate was also concentrated in vacuoand then suspended in ethanol with stirring, then filtered and dried invacuo to give another 7.92 g (33%) of tan solid.

¹H-NMR; IS-MS, m/e 298.3 (m+1); Analysis for C₇H₈NO₂IS: Calcd: C, 28.30;H, 2.71; N, 4.71; Found: C, 28.60; H, 2.64; N, 4.54.

D. 2-[(1-boc-Piperidin-4-ylcarbonyl)amino]-5-methylsulfonyliodobenzene

Using methods substantially equivalent to those described in Example25-D,2-[(1-Boc-piperidin-4-ylcarbonyl)amino]-5-methylsulfonyliodobenzene(6.88 g, 40%) was prepared from 2-iodo-4-(methylsulfonyl)aniline and1-Boc-piperidin-4-ylcarbonyl chloride.

¹H-NMR; IS-MS, m/e 507.0 (m−1)⁻; Analysis for C₁₈H₂₅N₂O₅IS: Calcd: C,42.53; H, 4.96; N, 5.51; Found: C, 42.29; H, 4.87; N, 5.43.

E. 2-[1-boc-Piperidin-4-yl]-6-methylsulfonyl-4H-3,1-benzoxazin-4-one

To a stirring solution of2-[(1-Boc-piperidin-4-ylcarbonyl)amino]-5-methylsulfonyliodobenzene(1.89 g, 3.72 mmol) in acetonitrile (50 mL) was added K₂CO₃ (2.53 g,18.6 mmol) followed by Pd(PPh₃)₄ (0.22 g, 0.19 mmol) and CuI (0.036 g,0.19 mmol). The mixture was placed under an atmosphere of CO and heatedto 75° C. After 2 h, the heat was removed and the mixture was dilutedwith ethyl acetate and washed with water, then brine The organic phasewas then dried with MgSO₄, filtered and concentrated in vacuo. Theresidue was chromatographed over silica gel, eluting with a gradient of10% to 20% ethyl acetate in dichloromethane The product containingfractions were combined and concentrated in vacuo to give 0.485 g (32%)of a white solid.

¹H-NMR; FD-MS, m/e 408.0 (m+); Analysis for C₁₉H₂₄N₂O₆S: Calcd: C,55.87; H, 5.92; N, 6.86; Found: C, 56.00; H, 5.94; N, 6.74.

F.2-[(1-boc-Piperidin-4-ylcarbonyl)amino]-N-(5-chloropyridin-2-yl)-5-methylsulfonylbenzamide

Using methods substantially equivalent to those described in Example51-D,2-[(1-Boc-piperidin-4-ylcarbonyl)amino]-N-(5-chloropyridin-2-yl)-5-methylsulfonylbenzamide(0.947 g, 89%) was prepared from2-[1-Boc-piperidin-4-yl]-6-methylsulfonyl-4H-3,1-benzoxazin-4-one

¹H-NMR; IS-MS, m/e 537.3 (m+1).

G.N-(5-Chloropyridin-2-yl)-2-[(piperidin-4-ylcarbonyl)amino]-5-methylsulfonylbenzamideTrifluoroacetate

Using methods substantially equivalent to those described in Example9-B,N-(5-chloropyridin-2-yl)-2-[(piperidin-4-ylcarbonyl)amino]-5-methylsulfonylbenzamidetrifluoroacetate (0.845 g, 91%) was prepared from2-[(1-Boc-piperidin-4-ylcarbonyl)amino]-N-(5-chloropyridin-2-yl)-5-methylsulfonylbenzamide

¹H-NMR; IS-MS, m/e 437.2 (m+1).

H.N-(5-Chloropyridin-2-yl)-2-[(1-isopropylpiperidin-4-ylcarbonyl)amino]-5-methylsulfonylbenzamideHydrochloride

Using methods substantially equivalent to those described in Example 27,N-(5-chloropyridin-2-yl)-2-[(1-isopropylpiperidin-4-ylcarbonyl)amino]-5-methylsulfonylbenzamidehydrochloride (0.375 g, 50%) was prepared fromN-(5-chloropyridin-2-yl)-2-[(piperidin-4-ylcarbonyl)amino]-5-methylsulfonylbenzamidetrifluoroacetate. The product was purified using reverse phase HPLC,eluting with a gradient of 10% through 40% acetonitrile in 0.05% aq HClover 200 min.

¹H-NMR; IS-MS, m/e 479.1 (m+1); Analysis forC₂₂H₂₇N₄O₄SCl.1.5HCl.0.2H₂O: Calcd: C, 49.18; H, 5.42; N, 10.43; Found:C, 49.14; H, 5.18; N, 10.10.

EXAMPLE 174 Preparation ofN-(5-Chloropyridin-2-yl)-5-(N,N-dimethylaminosulfonyl)-2-[(1-isopropylpiperidin-4-ylcarbonyl)amino]benzamideHydrochloride

A. 4-(N,N-Dimethylaminosulfonyl)nitrobenzene

To a stirring solution of dimethylamine (180 mL, 40% in water, 1.57 mol)in methanol (180 mL) at 0° C., was slowly added 4-nitrobenzenesulfonylchloride (69.5 g, 314 mmol). After complete addition, the cold bath wasremoved; and, after stirring overnight, the mixture was filtered and theprecipitate was washed with water and dried in vacuo to give 68 g (94%)of tan solid.

¹H-NMR; IS-MS, m/e 231.1 (m+1); Analysis for C₈H₁₀N₂O₄S: Calcd: C,41.73; H, 4.38; N, 12.17; Found: C, 41.44; H, 4.42; N, 12.04.

B. 4-(N,N-Dimethylaminosulfonyl)aniline

Using methods substantially equivalent to those described in Example173-B, 4-(N,N-dimethylaminosulfonyl)-aniline (11.7 g, 85%) was preparedfrom 4-(N,N-dimethylaminosulfonyl)nitrobenzene

¹H-NMR; IS-MS, m/e 201.2 (m+1); Analysis for C₈H₁₂N₂O₂S: Calcd: C,47.98; H, 6.04; N, 13.99; Found: C, 48.30; H, 6.03; N, 13.74.

C. 2-Iodo-4-(N,N-dimethylaminosulfonyl)aniline

Using methods substantially equivalent to those described in Example173-C, 2-iodo-4-(N,N-dimethylaminosulfonyl)aniline (12.8 g, 68%) wasprepared from 4-(N,N-dimethylaminosulfonyl)aniline

¹H-NMR; IS-MS, m/e 327.1 (m+1); Analysis for C₈H₁₁N₂O₂IS: Calcd: C,29.46; H, 3.40; N, 8.59; Found: C, 29.47; H, 3.16; N, 8.37.

D.2-[(1-boc-Piperidin-4-ylcarbonyl)amino]-5-(N,N-dimethylaminosulfonyl)iodobenzene

Using methods substantially equivalent to those described in Example25-D,2-[(1-Boc-piperidin-4-ylcarbonyl)amino]-5-(N,N-dimethylaminosulfonyl)iodobenzene(6.65 g, 40%) was prepared from2-iodo-4-(N,N-dimethylaminosulfonyl)aniline and1-Boc-piperidin-4-ylcarbonyl chloride.

¹H-NMR; IS-MS, m/e 536.2 (m−1)⁻; Analysis for C₁₉H₂₈N₃O₅IS: Calcd: C,42.46; H, 5.25; N, 7.82; Found: C, 42.32; H, 5.30; N, 7.65.

E.2-(1-boc-Piperidin-4-yl)-6-(N,N-dimethylaminosulfonyl)-4H-3,1-benzoxazin-4-one

Using methods substantially equivalent to those described in Example173-E,2-(1-Boc-piperidin-4-yl)-6-(N,N-dimethylaminosulfonyl)-4H-3,1-benzoxazin-4-one(0.87 g, 53%) was prepared from2-[(1-Boc-piperidin-4-ylcarbonyl)amino]-5-(N,N-dimethylaminosulfonyl)iodobenzene

¹H-NMR; Analysis for C₂₀H₂₇N₃O₆S: Calcd: C, 54.91; H, 6.22; N, 9.60;Found: C, 54.80; H, 6.28; N, 9.60.

F.2-[(1-boc-Piperidin-4-ylcarbonyl)amino]-N-(5-chloropyridin-2-yl)-5-(N,N-dimethylaminosulfonyl)benzamide

Using methods substantially equivalent to those described in Example51-D,2-[(1-Boc-piperidin-4-ylcarbonyl)amino]-N-(5-chloropyridin-2-yl)-5-(N,N-dimethylaminosulfonyl)benzamide(0.912 g, 85%) was prepared from2-(1-Boc-piperidin-4-yl)-6-(N,N-dimethylaminosulfonyl)-4H-3,1-benzoxazin-4-oneand 2-amino-5-chloropyridine

¹H-NMR; IS-MS, m/e 566.5 (m+1); Analysis for C₂₅H₃₂N₅O₆ClS: Calcd: C,53.05; H, 5.70; N, 12.37; Found: C, 53.45; H, 5.88; N, 11.79.

G.N-(5-Chloropyridin-2-yl)-5-(N,N-dimethylaminosulfonyl)-2-[(piperidin-4-ylcarbonyl)amino]benzamideTrifluoroacetate

Using methods substantially equivalent to those described in Example9-B,N-(5-chloropyridin-2-yl)-5-(N,N-dimethylaminosulfonyl)-2-[(piperidin-4-ylcarbonyl)amino]benzamidetrifluoroacetate (0.745 g, 92%) was prepared fromN-(5-chloropyridin-2-yl)-2-[(1-Boc-piperidin-4-ylcarbonyl)amino]-5-(N,N-dimethylaminosulfonyl)benzamide

¹H-NMR; IS-MS, m/e 466.1 (m+1); Analysis for C₂₀H₂₄N₅O₄SCl.CF₃OH: Calcd:C, 45.56; H, 4.34; N, 12.08; F, 9.83; Found: C, 45.85; H, 4.39; N,11.87; F, 10.68.

H.N-(5-Chloropyridin-2-yl)-5-(N,N-dimethylaminosulfonyl)-2-[(1-isopropylpiperidin-4-ylcarbonyl)amino]benzamideHydrochloride

Using methods substantially equivalent to those described in Example 27,N-(5-chloropyridin-2-yl)-5-(N,N-dimethylaminosulfonyl)-2-[(1-isopropylpiperidin-4-ylcarbonyl)amino]benzamidehydrochloride (0.605 g, 86%) was prepared fromN-(5-chloropyridin-2-yl)-5-(N,N-dimethylaminosulfonyl)-2-[(piperidin-4-ylcarbonyl)amino]benzamidetrifluoroacetate.

¹H-NMR; IS-MS, m/e 508.1 (m+1); Analysis forC₂₃H₃₀N₅O₄SCl.1.5HCl.1.8H₂O: Calcd: C, 46.41; H, 5.94; N, 11.77; Cl,14.89; Found: C, 46.70; H, 5.55; N, 11.47; Cl, 15.22.

EXAMPLE 175 Preparation ofN-(5-Chloropyridin-2-yl)-2-[(4-isopropylpiperazin-1-ylcarbonyl)amino]-5-(methylsulfonyl)benzamide

A. 2-[(4-boc-Piperazin-1-ylcarbonyl)amino]-5-(methylsulfonyl)iodobenzene

Using methods substantially equivalent to those described in Example51-A,2-[(1-Boc-piperazin-4-ylcarbonyl)amino]-5-(methylsulfonyl)iodobenzene(7.42 g, 86%) was prepared from Boc-piperazine and2-iodo-4-(methylsulfonyl)aniline

¹H-NMR; IS-MS, m/e 508.1 (m−1)⁻; Analysis for C₁₇H₂₄N₃O₅IS: Calcd: C,40.09; H, 4.75; N, 8.25; Found: C, 39.81; H, 4.67; N, 7.99.

B. 2-[1-boc-Piperazin-4-yl]-6-methylsulfonyl-4H-3,1-benzoxazin-4-one

Using methods substantially equivalent to those described in Example173-E, 2-[1-Boc-piperazin-4-yl]-6-methylsulfonyl-4H-3,1-benzoxazin-4-one(1.05 g, 63%) was prepared from2-[(1-Boc-piperazin-4-ylcarbonyl)amino]-5-(methylsulfonyl)iodobenzene

¹H-NMR; IS-MS, m/e 410.1 (m+1); Analysis for C₁₈H₂₃N₃O₆S: Calcd: C,52.80; H, 5.66; N, 10.26; Found: C, 52.59; H, 5.47; N, 9.97.

C.2-[(1-boc-Piperazin-4-ylcarbonyl)amino]-N-(5-chloropyridin-2-yl)-5-(methylsulfonyl)benzamide

Using methods substantially equivalent to those described in Example51-D,2-[(1-Boc-piperazin-4-ylcarbonyl)amino]-N-(5-chloropyridin-2-yl)-5-(methylsulfonyl)benzamide(0.565 g, 85%) was prepared from2-[1-Boc-piperazin-4-yl]-6-methylsulfonyl-4H-3,1-benzoxazin-4-one

¹H-NMR; IS-MS, m/e 538.1 (m+1).

D.N-(5-Chloropyridin-2-yl)-5-(methylsulfonyl)-2-[(piperazin-4-ylcarbonyl)amino]benzamidetrifluoroacetate

Using methods substantially equivalent to those described in Example9-B,N-(5-chloropyridin-2-yl)-5-(methylsulfonyl)-2-[(piperazin-4-ylcarbonyl)amino]benzamidetrifluoroacetate (1.02 g, 96%) was prepared from2-[(1-Boc-piperazin-4-ylcarbonyl)amino]-N-(5-chloropyridin-2-yl)-5-(methylsulfonyl)benzamide

¹H-NMR; IS-MS, m/e 438.0 (m+1).

E.N-(5-Chloropyridin-2-yl)-2-[(1-isopropylpiperazin-4-ylcarbonyl)amino]-5-(methylsulfonyl)benzamide

Using methods substantially equivalent to those described in Example 27,N-(5-chloropyridin-2-yl)-2-[(1-isopropylpiperazin-4-ylcarbonyl)amino]-5-(methylsulfonyl)benzamide(0.34 g, 77%) was prepared fromN-(5-chloropyridin-2-yl)-5-(methylsulfonyl)-2-[(piperazin-4-ylcarbonyl)amino]benzamidetrifluoroacetate.

¹H-NMR; IS-MS, m/e 480.1 (m+1); Analysis for C₂₁H₂₆N₅O₄SCl: Calcd: C,52.55; H, 5.46; N, 14.59; Found: C, 52.25; H, 5.33; N, 14.23.

EXAMPLE 176 Preparation ofN-(5-Chloropyridin-2-yl)-5-(N,N-dimethylaminosulfonyl)-2-[(4-isopropylpiperazin-1-ylcarbonyl)amino]benzamideHydrochloride

A.2-[(1-boc-Piperazin-4-ylcarbonyl)amino]-5-(N,N-dimethylaminosulfonyl)iodobenzene

Using methods substantially equivalent to those described in Example51-A,2-[(1-Boc-piperazin-4-ylcarbonyl)amino]-5-(N,N-dimethylaminosulfonyl)iodobenzene(6.58 g, 79%) was prepared from2-iodo-4-(N,N-dimethylaminosulfonyl)aniline

¹H-NMR; IS-MS, m/e 537.1 (m−1)⁻.

B.2-(1-boc-Piperazin-4-yl)-6-(N,N-dimethylaminosulfonyl)-4H-3,1-benzoxazin-4-one

Using methods substantially equivalent to those described in Example173-E,2-(1-Boc-piperazin-4-yl)-6-(N,N-dimethylaminosulfonyl)-4H-3,1-benzoxazin-4-one(0.98 g, 60%)was prepared from2-[(1-Boc-piperazin-4-ylcarbonyl)amino]-5-(N,N-dimethylaminosulfonyl)iodobenzene

¹H-NMR; IS-MS, m/e 438.1 (m+1); Analysis for C₁₉H₂₆N₄O₆S: Calcd: C,52.04; H, 5.98; N, 12.78; Found: C, 52.10; H, 5.90; N, 12.73.

C.2-[(1-boc-Piperazin-4-ylcarbonyl)amino]-N-(5-chloropyridin-2-yl)-5-(N,N-dimethylaminosulfonyl)benzamide

Using methods substantially equivalent to those described in Example51-D,2-[(1-Boc-piperazin-4-ylcarbonyl)amino]-N-(5-chloropyridin-2-yl)-5-(N,N-dimethylaminosulfonyl)benzamide(0.963 g, 82%) was prepared from2-(1-Boc-piperazin-4-yl)-6-(N,N-dimethylaminosulfonyl)-4H-3,1-benzoxazin-4-one

¹H-NMR; IS-MS, m/e 567.1 (m+1).

D.N-(5-Chloropyridin-2-yl)-5-(N,N-dimethylaminosulfonyl)-2-[(piperazin-4-ylcarbonyl)amino]benzamideTrifluoroacetate

Using methods substantially equivalent to those described in Example9-B,N-(5-chloropyridin-2-yl)-5-(N,N-dimethylaminosulfonyl)-2-[(piperazin-4-ylcarbonyl)amino]benzamidetrifluoroacetate (0.908 g, 94%) was prepared from2-[(1-Boc-piperazin-4-ylcarbonyl)amino]-N-(5-chloropyridin-2-yl)-5-(N,N-dimethylaminosulfonyl)benzamide

¹H-NMR; IS-MS, m/e 467.1 (m+1); Analysis for C₁₉H₂₃N₆O₄SCl.1.1TFA:Calcd: C, 42.98; H, 4.10; N, 14.19; F, 10.58; Found: C, 43.05; H, 4.01;N, 13.85; F, 10.40.

E.N-(5-Chloropyridin-2-yl)-5-(N,N-dimethylaminosulfonyl)-2-[(1-isopropylpiperazin-4-ylcarbonyl)amino]benzamideHydrochloride

Using methods substantially equivalent to those described in Example 27,N-(5-chloropyridin-2-yl)-5-(N,N-dimethylaminosulfonyl)-2-[(1-isopropylpiperazin-4-ylcarbonyl)amino]benzamidehydrochloride (0.616 g, 84%) was prepared fromN-(5-chloropyridin-2-yl)-5-(N,N-dimethylaminosulfonyl)-2-[(piperazin-4-ylcarbonyl)amino]benzamidetrifluoroacetate.

¹H-NMR; IS-MS, m/e 509.1 (m+1); Analysis forC₂₂H₂₉N₆04SCl.1.8HCl.1.6H₂O: Calcd: C, 43.65; H, 5.70; N, 13.89; Cl,16.40; Found: C, 43.72; H, 5.56; N, 13.54; Cl, 16.46.

EXAMPLE 177 Preparation ofN-(5-Chloropyridin-2-yl)-2-(1-isopropylpiperidin-4-ylmethylamino)-4-methoxycarbonylbenzamide

A. N-(5-Chloropyridin-2-yl)-4-methoxycarbonyl-2-nitrobenzamide

Using a similar procedure to that described in Example 1-A,4-methoxycarbonyl-2-nitrobenzoic acid (1.87 g, 8.31 mmol) and2-amino-5-chloropyridine (1.16 g, 9.14 mmol) afforded 2.05 g (74%) ofthe title compound.

¹H-NMR, IR; IS-MS, m/e 336 (m+1); Analysis for C₁₄H₁₀ClN₃O₅: Calcd: C,50.09; H, 3.00; N, 12.52; Found: C, 49.73; H, 2.94; N, 12.19.

B. 2-Amino-N-(5-chloropyridin-2-yl)-4-methoxycarbonylbenzamide

Using a similar procedure to that described in Example 2-B,N-(5-chloropyridin-2-yl)-4-methoxycarbonyl-2-nitrobenzamide (2.00 g,5.99 mmol) afforded 1.50 g (82%) of the title compound.

¹H-NMR, IR; IS-MS, m/e 305 (m+1); Analysis for C₁₄H₁₂ClN₃O₃: Calcd: C,55.00; H, 3.96; N, 13.74; Found: C, 54.43; H, 3.68; N, 13.64.

C.N-(5-Chloropyridin-2-yl)-4-methoxycarbonyl-2-(piperidin-4-ylmethylamino)benzamide

Using a similar procedure to that described in Example 47-C&D,2-amino-N-(5-chloropyridin-2-yl)-4-methoxycarbonylbenzamide (1.00 g,3.28 mmol), 1-tert-butoxycarbonylpiperidine-4-carboxaldehyde (1.05 g,4.92 mmol), and borane trimethylamine complex (717 mg, 9.94 mmol)afforded 1.10 g (84%) of the title compound.

¹H-NMR; IS-MS, m/e 403 (m+1).

D.N-(5-Chloropyridin-2-yl)-2-(1-isopropylpiperidin-4-ylmethylamino)-4-methoxycarbonylbenzamide

Using a similar procedure to that described in Example 9-C,N-(5-chloropyridin-2-yl)-4-methoxycarbonyl-2-(piperidin-4-ylmethylamino)benzamide(230 mg, 0.572 mmol) afforded 168 mg (66%) of the title compound.

¹H-NMR; IS-MS, m/e 445 (m+1).

EXAMPLE 178 Preparation ofN-(5-Chloropyridin-2-yl)-4-methoxycarbonyl-2-[1-(4-pyridinyl)piperidin-4-ylmethylamino]benzamide

Using a similar procedure to that described in Example 52,N-(5-chloropyridin-2-yl)-4-methoxycarbonyl-2-(piperidin-4-ylmethylamino)benzamide(700 mg, 1.74 mmol) afforded 380 mg (45%) of the title compound.

¹H-NMR, IR; IS-MS, m/e 480 (m+1); Analysis for C₂₅H₂₆ClN₆O₃: Calcd: C,62.56; H, 5.46; N, 14.59; Found: C, 62.58; H, 5.52; N, 14.51.

EXAMPLE 179 Preparation of4-Carboxy-N-(5-chloropyridin-2-yl)-2-(1-isopropylpiperidin-4-ylmethylamino)benzamideHydrochloride

A solution ofN-(5-chloropyridin-2-yl)-2-(1-isopropylpiperidin-4-ylmethylamino)-4-methoxycarbonylbenzamide(100 mg, 0.225 mmol) in 4:1 tetrahydrofuran:water (2.5 mL) was treatedwith lithium hydroxide (20 mg, 0.90 mmol). After 17 h, the pH of themixture was adjusted to 2-3 by addition of 1 N HCl. The mixture was thenconcentrated and the residue purified by RPHPLC affording 32 mg (30%) ofthe title compound as a hydrochloride salt.

¹H-NMR; IS-MS, m/e 431 (m+1).

EXAMPLE 180 Preparation of4-Carboxy-N-(5-chloropyridin-2-yl)-2-[1-(4-pyridinyl)piperidin-4-ylmethylamino]benzamideDihydrochloride

Using a similar procedure to that described in Example 179,N-(5-chloropyridin-2-yl)-4-methoxycarbonyl-2-[1-(4-pyridinyl)piperidin-4-ylmethylamino]benzamide(180 mg, 0.376 mmol) afforded 125 mg (62%) of the title compound as ahydrochloride salt.

¹H-NMR, IR; IS-MS, m/e 466 (m+1) Analysis for C₂₄H₂₄ClN₅O₃ (3.0 HCl, 1.5H₂O): Calcd: C, 47.86; H, 5.02; N, 11.63; Found: C, 47.81; H, 4.91; N,11.43.

EXAMPLE 181 Preparation ofN-(5-Chloropyridin-2-yl)-2-[1-(2-thiocarbamoylpyridin-4-yl)piperidin-4-ylmethylamino]benzamide

A pressure tube was charged withN-(5-chloropyridin-2-yl)-2-[1-(2-cyanopyridin-4-yl)piperidin-4-ylmethylamino]benzamide(50 mg, 0.11 mmol) and 1:2 methanol:tetrahydrofuran (3 mL); and thesolution was treated with ammonia(g), sealed, and allowed to stir for 2days. The mixture was then treated with hydrogen sulfide (g), sealed andallowed to stir for 2 days. The mixture was concentrated and the residuepurified by column chromatography (SiO₂: 2% methanol in methylenechloride) affording 38 mg (70%) of the title compound.

¹H-NMR, IR; IS-MS, m/e 481 (m+1); Analysis for C₂₄H₂₅ClN₆OS0.25H₂O:Calcd: C, 59.37; H, 5.29; N, 17.31; Found: C, 59.04; H, 5.04; N, 16.65.

EXAMPLE 182 Preparation ofN-(5-Chloropyridin-2-yl)-2-[1-(2-carbamoylpyridin-4-yl)piperidin-4-ylmethylamino]benzamide

A pressure tube was charged withN-(5-chloropyridin-2-yl)-2-[[1-(3-methoxycarbonylpyridin-4-yl)piperidin-4-ylmethyl]amino]benzamide(50 mg, 0.10 mmol) and 2 N ammonia in methanol (5 mL), sealed, andplaced in a 110° C. bath. After 4 h, the mixture was transferred to a60° C. bath. After 3 days, the mixture was cooled, concentrated, and theresidue purified by column chromatography (SiO₂, 2% methanol inmethylene chloride) affording 48 mg (96%) of the title compound.

¹H-NMR, IR; IS-MS, m/e 465 (m+1).

EXAMPLE 183 Preparation ofN-(5-Chloropyridin-2-yl)-2-[1-[2-(hydroxymethyl)pyridin-4-yl]piperidin-4-ylmethylamino]benzamideTrifluoroacetic Acid Salt

A solution ofN-(5-chloropyridin-2-yl)-2-[[1-(3-methoxycarbonylpyridin-4-yl)piperidin-4-ylmethyl]amino]benzamide(200 mg, 0.42 mmol) in tetrahydrofuran was treated with lithium aluminumhydride (1 M in THF, 0.83 mL, 0.83 mmol). After 2 h, additional lithiumaluminum hydride was introduced (0.42 mL, 0.42 mmol). After 0.5 h, themixture was treated with water, 1 N NaOH, and a saturated aqueoussolution of sodium potassium tartrate. The mixture was washed with EtOAc(3×) and the combined extracts were dried with magnesium sulfate,filtered, concentrated, and the residue purified by RPHPLC affording 17mg (7%) of the title compound as a trifluoroacetate salt.

¹H-NMR, IR; IS-MS, m/e 452 (m+1); Analysis for C₂₆H₂₇ClF₃N₅O₄(6.0H₂O):Calcd: C, 46.33; H, 5.83; N, 10.38; Found: C, 46.08; H, 5.68; N, 11.01.

EXAMPLE 184 Preparation of5-Chloro-N-(5-methylpyridin-2-yl)-2-{[-(tetrahydrothiopyran-4-yl)piperidin-4-yl]methylamino}benzamide

5-Chloro-N-(5-methylpyridin-2-yl)-2-[(4-piperidinylmethyl)amino]benzamidefrom Example 99-A (0.45 g, 1.25 mmol) was dissolved in 95:5methanol-acetic acid (10 mL), followed by addition oftetrahydrothiopyran-4-one (1.46 g, 12.6 mmol) and sodiumcyanoborohydride (5.0 mL of a 1 M solution in tetrahydrofuran, 6.0mmol). After stirring at 50° C. for 96 h, the mixture was concentratedin vacuo; and the residue was directly subjected to silica gelchromatography. Elution with 9:1 dichloromethane-methanol provided 0.23g (40%) of the title product as a yellow solid.

¹NMR; mp 173-176° C.; MS, m/e 459.3 (M+). Analysis for C₂₄H₃₁ClN₄OS:Calcd: C, 62.80; H, 6.81; N, 12.20; Found: C, 62.75; H, 6.71; N, 12.05.

EXAMPLE 185 Preparation of5-Chloro-N-(5-methylpyridin-2-yl)-2-{[1-(1,1-dioxohexahydro-1λ⁶-thiopyran-4-yl)piperidine-4-yl]methylamino}benzamide

To a solution of5-chloro-N-(5-methylpyridin-2-yl)-2-{[1-(tetrahydrothiopyran-4-yl)piperidin-4-yl]methylamino}benzamidefrom Example 184 (1.0 g, 2.2 mmol) in 20 mL of dichloromethane, 50%m-chloroperoxybenzoic acid was added (1.88 g, 10.9 mmol). The solutionwas stirred at room temperature overnight, then concentrated in vacuoand taken up in a few mL of methanol. The crude solution was directlyapplied to a 10 g SCX column, flushed with methanol, and eluted with 9:1dichloromethane-2 M ammonia in methanol. Two products were isolated; theminor one (18 mg of an orange solid) was identified as the title productby MS.

mp 154-156° C.; ^(1,13)NMR, IR; MS, m/e 491.0 (M+).

EXAMPLE 186 Preparation of5-Chloro-N-(5-methylpyridin-2-yl)-2-[(1-cycloheptylpiperidin-4-yl)methylamino]benzamide

A solution of5-chloro-N-(5-methylpyridin-2-yl)-2-[(4-piperidinylmethyl)amino]benzamidefrom Example 99-A (0.45 g, 1.25 mmol) in 10 mL of 95:5 methanol-aceticacid was treated with excess cycloheptanone (1.48 mL, 12.5 mmol),followed by sodium cyanoborohydride (5.0 ml of a 1 M solution intetrahydrofuran, 6.0 mmol). After stirring at 50° C. for 96 h, themixture was concentrated in vacuo; and the residue was subjected tosilica gel chromatography. Elution with 9:1 dichloromethane-methanolprovided 0.41 g (72%) of the title compound as an off-white solid.

¹NMR; mp 159-161° C.; MS, m/e 455.3 (M+). Analysis forC₂₆H₃₅ClN₄O.0.5H₂O: Calcd: C, 67.30; H, 7.82; N, 12.07; Found: C, 67.85;H, 7.48; N, 12.09.

EXAMPLE 187 Preparation of5-Chloro-N-(5-methylpyridin-2-yl)-2-[(1-sec-butylpiperidin-4-yl)methylamino]benzamide

A solution of5-chloro-N-(5-methylpyridin-2-yl)-2-[(4-piperidinylmethyl)amino]benzamidefrom Example 99-A (0.45 g, 1.25 mmol) in 10 mL of 95:5 methanol-aceticacid was treated with methylethyl ketone (1.12 mL, 12.5 mmol), followedby sodium cyanoborohydride (5.0 ml of a 1 M solution in tetrahydrofuran,6.0 mmol). After stirring at 50° C. for 96 h, the mixture wasconcentrated in vacuo; and the residue was subjected to silica gelchromatography. Elution with 9:1 dichloromethane-methanol afforded 0.26g (50%) of the title compound as a tan solid.

¹NMR; mp 126-128° C.; MS, m/e 415.2 (M+). Analysis for C₂₃H₃₁ClN₄O.1H₂O:Calcd: C, 63.80; H, 7.68; N, 12.93; Found: C, 63.99; H, 7.20; N, 12.93.

EXAMPLE 188 Preparation of5-Chloro-N-(5-methylpyridin-2-yl)-2-{[1-(3-pentyl)piperidin-4-yl]methylamino}benzamide

A solution of5-chloro-N-(5-methylpyridin-2-yl)-2-[(4-piperidinylmethyl)amino]benzamidefrom Example 99-A (0.45 g, 1.25 mmol) in 10 mL of 95:5 methanol-aceticacid was treated with excess 3-pentanone (1.32 mL, 12.5 mmol), followedby sodium cyanoborohydride (5.0 ml of a 1 M solution in tetrahydrofuran,6.0 mmol). After stirring at 50° C. for 96 h, the mixture wasconcentrated in vacuo; and the residue was subjected to silica gelchromatography. Elution with 9:1 dichloromethane-methanol furnished 0.21g (39%) of the title compound as a yellow solid.

¹NMR; mp 122-124° C.; MS, m/e 429.3 (M+). Analysis for C₂₃H₃₁ClN₄O:Calcd: C, 67.19; H, 7.75; N, 13.06; Found: C, 66.71; H, 7.59; N, 12.96.

EXAMPLE 189 Preparation of5-Chloro-N-(5-methylpyridin-2-yl)-2-[(1-cyclohexylpiperidin-4-yl)methylamino]benzamide

A solution of5-chloro-N-(5-methylpyridin-2-yl)-2-[(4-piperidinylmethyl)amino]benzamidefrom Example 99-A (0.45 g, 1.25 mmol) in 10 mL of 95:5 methanol-aceticacid was treated with excess cyclohexanone (1.30 mL, 12.5 mmol),followed by sodium cyanoborohydride (5.0 ml of a 1 M solution intetrahydrofuran, 6.0 mmol). After stirring at 50° C. for 48 h, themixture was concentrated in vacuo; and the residue was subjected tosilica gel chromatography. Elution with 9:1 dichloromethane-methanolafforded 0.34 g (62%) of the title compound as a yellow solid.

¹NMR; mp 176.4-177.8° C.; MS, m/e 441.3 (M+). Analysis for C₂₅H₃₃ClN₄O:Calcd: C, 68.09; H, 7.54; N, 12.70; Found: C, 68.37; H, 7.67; N, 12.78.

EXAMPLE 190 Preparation of5-Chloro-N-(5-methylpyridin-2-yl)-2-{[1-(tetrahydropyran-4-yl)piperidin-4-yl]methylamino}benzamide

A solution of5-chloro-N-(5-methylpyridin-2-yl)-2-[(4-piperidinylmethyl)amino]benzamidefrom Example 99-A (0.45 g, 1.25 mmol) in 10 mL of 95:5 methanol-aceticacid was treated with excess tetrahydro-4H-pyran-4-one (1.16 mL, 12.5mmol), followed by sodium cyanoborohydride (5.0 ml of a 1 M solution intetrahydrofuran, 6.0 mmol). After stirring at 50° C. for 36 h, themixture was concentrated in vacuo; and the residue was subjected tosilica gel chromatography. Elution with 9:1 dichloromethane-2 M ammoniain methanol afforded 0.51 g (93%) of the title compound as a yellowsolid.

¹NMR; mp 166-168° C.; MS, m/e 443.2 (M+). Analysis for C₂₄H₃₁ClN₄O₂:Calcd: C, 65.07; H, 7.05; N, 12.65; Found: C, 65.04; H, 6.84; N, 12.56.

EXAMPLE 191 Preparation of5-Chloro-N-(5-methylpyridin-2-yl)-2-{[1-(tetrahydrothiophen-3-yl)piperidin-4-yl]methylamino}benzamide

A solution of5-chloro-N-(5-methylpyridin-2-yl)-2-[(4-piperidinylmethyl)amino]benzamidefrom Example 99-A (0.45 g, 1.25 mmol) in 10 mL of 95:5 methanol-aceticacid was treated with excess tetrahydrothiophen-3-one (1.07 mL, 12.5mmol), followed by sodium cyanoborohydride (5.0 ml of a 1 M solution intetrahydrofuran, 6.0 mmol). After stirring at 50° C. for 96 h, themixture was concentrated in vacuo; and the residue was subjected tosilica gel chromatography. Elution with 9:1 dichloromethane-2 M ammoniain methanol afforded 0.43 g (77%) of the title compound as a yellowsolid.

¹NMR; mp 151-153° C.; MS, m/e 445.2 (M+). Analysis for C₂₃H₂₉ClN₄OS:Calcd: C, 62.08; H, 6.57; N, 12.59; Found: C, 62.83; H, 6.63; N, 12.52.

EXAMPLE 192 Preparation of5-Chloro-N-(5-methylpyridin-2-yl)-2-{[1-(1,1-dioxotetrahydro-1λ⁶-thiophen-3-yl)piperidin-4-yl]methylamino}benzamide

A solution of5-chloro-N-(5-methylpyridin-2-yl)-2-{[1-(tetrahydrothiophen-3-yl)piperidin-4-yl]methylamino}benzamidefrom example 191 (0.1 g, 0.22 mmol) in dichloromethane at 0° C. wastreated with m-chloroperoxybenzoic acid (84 mg, 0.24 mmol). After 5 h at0° C., an identical portion of 50% m-chloroperoxybenzoic acid was added.The reaction mixture was kept at 0° C. overnight, before directlyapplying it to an SCX column. After a thorough wash with methanol,elution with 9:1 dichloromethane-2 M ammonia in methanol provided acrude product, which was submitted to preparative thin layerchromatography. Elution with 9:1 dichloromethane-methanol provided threedifferent product bands. The product with the highest R^(f) value wasassigned to the title sulfone by LC-MS (method B). Isolation of thisband provided 30 mg (30%) of the title compound as a yellow foam.

LC-MS: 86% pure, R_(t)=5.425 min, m/e 477.1 (M). ¹NMR, IR.

EXAMPLE 193 Preparation of5-Chloro-N-(5-methylpyridin-2-yl)-2-[(1-cyclopentylpiperidin-4-yl)methylamino]benzamide

A solution of5-chloro-N-(5-methylpyridin-2-yl)-2-[(4-piperidinylmethyl)amino]benzamidefrom Example 99-A (0.45 g, 1.25 mmol) in 10 mL of 95:5 methanol-aceticacid was treated with excess cyclopentanone (1.11 mL, 12.5 mmol),followed by sodium cyanoborohydride (5.0 ml of a 1 M solution intetrahydrofuran, 6.0 mmol). After stirring at 50° C. for 36 h, themixture was concentrated in vacuo; and the residue was subjected tosilica gel chromatography. Elution with 9:1 dichloromethane-2 M ammoniain methanol afforded 0.31 g (58%) of the title compound as a yellowsolid.

¹NMR; mp 150-152° C.; MS, m/e 427.2 (M+). Analysis for C₂₄H₃₁ClN₄O:Calcd: C, 67.51; H, 7.32; N, 13.12; Found: C, 66.91; H, 7.12; N, 13.17.

EXAMPLE 194 Preparation of5-Chloro-N-(5-methylpyridin-2-yl)-2-{[1-(1-cyclopropylethyl)piperidin-4-yl]methylamino}benzamideHydrochloride

A solution of5-chloro-N-(5-methylpyridin-2-yl)-2-[(4-piperidinylmethyl)amino]benzamidefrom Example 99-A (0.45 g, 1.25 mmol) in 10 mL of 95:5 methanol-aceticacid was treated with excess cyclopropylmethyl ketone (1.24 mL, 12.5mmol), followed by sodium cyanoborohydride (5.0 ml of a 1 M solution intetrahydrofuran, 6.0 mmol). After stirring at 50° C. for 48 h, themixture was concentrated in vacuo; and the residue was subjected tosilica gel chromatography. Elution with 9:1 dichloromethane-2 M ammoniain methanol afforded 0.27 g of impure free-base product. Subsequentpurification by reverse phase HPLC provided 34 mg of the pure titlehydrochloride as a yellow solid.

¹NMR; MS, m/e 461.0 (M+). Analysis for C₂₄H₃₁ClN₄O.2.5HCl: Calcd: C,55.63; H, 6.52; N, 10.81; Found: C, 56.30; H, 6.54; N, 10.32.

EXAMPLE 195 Preparation of5-Chloro-N-(5-chloropyridin-2-yl)-2-{[1-(1-cyclopropylethyl)piperidin-4-yl]methylamino}benzamide

A solution of5-chloro-N-(5-chloropyridin-2-yl)-2-[(4-piperidinylmethyl)amino]benzamidefrom Example 60 (60 mg, 0.16 mmol) in 500 μL of 95:5 methanol-aceticacid was prepared in a 4 mL sealable vial. To this was added excesscyclopropylmethyl ketone (156 μL, 1.6 mmol), followed by sodiumcyanoborohydride (630 μl of a 1 M solution in tetrahydrofuran, 0.63mmol). The vial was capped and placed in a shaker, heated at 50° C. for96 h. The reaction mixture was then applied to an SCX column, washedwith methanol and eluted with 1 N ammonia in methanol. The yellowfractions were combined and concentrated in vacuo to a dry residue,which was purified by preparative thin layer chromatography. Elutionwith 9:1 dichloromethane-methanol provided 13 mg (18%) of a yellowresidue, which was identified as the title compound by LC-MS (Method A).

¹NMR; LC-MS: 97% pure, R_(t)=7.958 min, m/e 447.1 (M+).

EXAMPLE 196 Preparation of5-chloro-N-(5-chloropyridin-2-yl)-2-[(1-cyclopentylpiperidin-4-yl)methylamino]benzamide

In a manner similar to that described in Example 195,5-chloro-N-(5-chloropyridin-2-yl)-2-(4-piperidinylmethyl)amino]benzamidefrom Example 60 (60 mg, 0.16 mmol) was converted to the title compound(46 mg, 65%), which was identified as by LC-MS (Method A).

¹NMR; mp 169.5-171.0° C.; LC-MS: 99% pure, R_(t)=7.911 min, m/e 447.1(M+). Analysis for C₂₃H₂₈Cl₂N₄O: Calcd: C, 61.75; H, 6.31; N, 12.52;Found: C, 61.19; H, 6.21; N, 12.25.

EXAMPLE 197 Preparation of5-Chloro-N-(5-chloropyridin-2-yl)-2-[(1-cyclohexylpiperidin-4-yl)methylamino]benzamide

In a manner similar to that described in Example 195,5-chloro-N-(5-chloropyridin-2-yl)-2-[(4-piperidinylmethyl)amino]benzamidefrom Example 60 (60 mg, 0.16 mmol) was converted to the title compound(49 mg, 67%), which was identified by LC-MS (Method A).

¹NMR; mp 186-188° C.; LC-MS: 90% pure, R_(t)=8.310 min, m/e 461.1 (M+).Analysis for C₂₄H₃₀Cl₂N₄O: Calcd: C, 62.47; H, 6.55; N, 12.14; Found: C,62.21; H, 6.27; N, 12.20.

EXAMPLE 198 Preparation of5-Chloro-N-(5-chloropyridin-2-yl)-2-{[1-(tetrahydropyran-4-yl)piperidin-4-yl]methylamino}benzamide

In a manner similar to that described in Example 195,5-chloro-N-(5-chloropyridin-2-yl)-2-[(4-piperidinylmethyl)amino]benzamidefrom Example 60 (60 mg, 0.16 mmol) was converted to the title compound(60 mg, 82%), which was identified by LC-MS (Method A).

¹NMR; mp 192-194° C.; LC-MS: 94% pure, R_(t)=7.169 min, m/e 463.1 (M+).Analysis for C₂₃H₂₈Cl₂N₄O₂.0.1CH₂Cl₂: Calcd: C, 58.90; H, 6.00; N,11.84; Found: C, 58.83; H, 6.04; N, 11.66.

EXAMPLE 199 Preparation of5-Chloro-N-(5-chloropyridin-2-yl)-2-[(1-cycloheptylpiperidin-4-yl)methylamino]benzamide

In a manner similar to that described in Example 195,5-chloro-N-(5-chloropyridin-2-yl)-2-[(4-piperidinylmethyl)amino]benzamidefrom Example 60 (60 mg, 0.16 mmol) was converted to the title compound(44 mg, 59%), which was identified by LC-MS (Method A).

¹NMR; mp 170.0-171.5° C.; LC-MS: 98% pure, R_(t)=8.652 min, m/e 475.2(M+). Analysis for C₂₅H₃₂Cl₂N₄O: Calcd: C, 63.15; H, 6.78; N, 11.78;Found: C, 62.93; H, 6.82; N, 11.69.

EXAMPLE 200 Preparation of5-Chloro-N-(5-chloropyridin-2-yl)-2-{[1-(4,4,4-trifluorobut-2-yl)piperidin-4-yl]methylamino}benzamide

A solution of5-chloro-N-(5-chloropyridin-2-yl)-2-[(4-piperidinylmethyl)amino]benzamidefrom Example 60 (0.37 g, 1 mmol) in 11 mL of 95:5 methanol-acetic acidwas treated with excess of 4,4,4-trifluorobutan-2-one (1 g, 7.9 mmol),followed by sodium cyanoborohydride (0.25 g, 4 mmol). The reactionmixture was heated at 70° C. overnight, after which a small trace of thedesired product was detected by LC-MS analysis. The crude reactionmixture was directly submitted to silica gel chromatography; elutionwith 9:1 dichloromethane-2 M ammonia in methanol provided a small amountof impure product. Further purification by preparative thin layerchromatography afforded 10 mg of the title compound, identified by LC-MS(Method A).

LC-MS: 91% pure, R_(t)=4.967 min, m/e 489.1 (M+).

EXAMPLE 201 Preparation of5-Chloro-N-(5-chloropyridin-2-yl)-2-{[1-(tetrahydrothiophen-3-yl)piperidin-4-yl]methylamino}benzamide

In a manner similar to that described in Example 191,5-chloro-N-(5-chloropyridin-2-yl)-2-[(4-piperidinylmethyl)amino]benzamidefrom Example 60 (2.0 g, 5.3 mmol) was converted to the title compound(1.7 g, 69%), which was identified by LC-MS (method A).

¹NMR, IR; mp 177.6-180.6° C.; LC-MS: 98% pure, R_(t)=4.720 min, m/e465.2 (M+). Analysis for C₂₂H₂₆Cl₂N₄OS: Calcd: C, 56.77; H, 5.63; N,12.04; Found: C, 56.64; H, 5.67; N, 12.08.

EXAMPLE 202 Preparation of5-Chloro-N-(5-chloropyridin-2-yl)-2-{[1-(1,1-dioxohexahydro-1λ⁶-thiopyran-4-yl)piperidine-4-yl]-methylamino}benzamide

To a solution of5-chloro-N-(5-chloropyridin-2-yl)-2-{[1-(1,1-hexahydro-1λ⁶-thiopyran-4-yl)piperidine-4-yl]-methylamino}benzamide(0.13 g, 0.27 mmol) from Example 112 in 9 mL of chloroform at 0° C., 50%m-chloroperoxybenzoic acid was added (0.13 g, 0.74 mmol). After 4 h at0° C., the reaction mixture was warmed to room temperature and keptstirring overnight. Since examination of the reaction mixture by LC-MSindicated the presence of starting material, more 50%m-chloroperoxybenzoic acid was added and the reaction was stirred atroom temperature for an additional 24 h. The crude mixture was thendirectly submitted to silica gel chromatography, eluting with 19:1dichloromethane-2 M ammonia in methanol. Two product bands where thusisolated and identified by LC-MS analysis (method B): the high R^(f)band corresponded to the title sulfone, and the lower R^(f) band wasassigned as the corresponding sulfoxide described in Example 203. Thecrude sulfone was further purified by preparative thin layerchromatography, providing the pure title compound (41 mg, 30%) as awhite solid.

¹NMR; LC-MS: 95% pure, R_(t)=6.919 min, m/e 511.2 (M+).

EXAMPLE 203 Preparation of5-Chloro-N-(5-chloropyridin-2-yl)-2-{[1-(1-oxohexahydro-1λ⁴-thiopyran-4-yl)piperidin-4-yl]methylamino}benzamide

As described in Example 202,5-chloro-N-(5-chloropyridin-2-yl)-2-{[1-(1,1-hexahydro-1λ⁶-thiopyran-4-yl)piperidine-4-yl]methylamino}benzamidewas converted to the title sulfoxide upon treatment with 50%m-chloroperoxybenzoic acid. The crude product was further purified bypreparative thin layer chromatography, which afforded the pure titlecompound (58 mg, 43%) as a white solid.

¹NMR; LC-MS: 95% pure, R_(t)=6.397 min, m/e 495.2 (M+).

EXAMPLE 204 Preparation ofN-(5-Chloropyridin-2-yl)-5-methyl-2-[(4-piperidinylmethyl)amino]benzamide

In a manner similar to that described in Example 59,2-amino-N-(5-chloropyridin-2-yl)-5-methylbenzamide (4.0 g, 15.3 mmol)was converted to the title compound (3.7 g, 67%), which was isolated asa pale-yellow solid.

¹NMR; mp 229-231° C.; MS, m/e 358.9 (M+).

EXAMPLE 205 Preparation ofN-(5-Chloropyridin-2-yl)-2-[(1-isopropylpiperidin-4-yl)methylamino]-5-methylbenzamide

A solution ofN-(5-chloropyridin-2-yl)-2-[(4-piperidinylmethyl)amino]-5-methylbenzamidefrom Example 204 (1.0 g, 2.78 mmol) in 20 mL of acetone and 6 mL of 95:5methanol-acetic acid was treated with sodium cyanoborohydride (0.70 g,11.1 mmol). After stirring at room temperature for 24 h, the reactionmixture was applied to a 10 g SCX column, washed with methanol andeluted with 1 N ammonia in methanol. The yellow fractions were combinedand concentrated in vacuo, affording 0.76 g (69%) of the title compoundas a yellow solid.

¹NMR; mp 172-174° C.; MS, m/e 401.3 (M+). Analysis for C₂₂H₂₉ClN₄O:Calcd: C, 65.90; H, 7.29; N, 13.97; Found: C, 65.65; H, 6.95; N, 13.83.

EXAMPLE 206 Preparation ofN-(5-Chloropyridin-2-yl)-2-{[1-(1-cyclopropylethyl)piperidin-4-yl]methylamino}-5-methylbenzamide

A solution ofN-(5-chloropyridin-2-yl)-2-[(4-piperidinylmethyl)amino]-5-methylbenzamidefrom Example 204 (1.0 g, 2.78 mmol) in 6 mL of 95:5 methanol-acetic acidwas treated with excess cyclopropylmethyl ketone (5.52 mL, 55.6 mmol),followed by sodium cyanoborohydride (0.65 g, 10.3 mmol). After stirringat room temperature for 24 hr, the reaction mixture was concentrated invacuo; and the residue was subjected to silica gel chromatography.Elution with 9:1 dichloromethane-methanol afforded 0.76 g (64%) of thetitle compound as a yellow solid.

¹NMR; mp 79-81° C.; MS, m/e 427.0 (M+). Analysis forC₂₄H₃₁ClN₄O.0.25CH₂Cl₂: Calcd: C, 64.51; H, 7.04; N, 12.38; Found: C,64.59; H, 7.82; N, 14.42.

EXAMPLE 207 Preparation ofN-(5-Chloropyridin-2-yl)-2-[(1-cyclohexylpiperidin-4-yl)methylamino]-5-methylbenzamide

In a manner similar to that described in Example 206,N-(5-chloropyridin-2-yl)-2-[(4-piperidinylmethyl)amino]-5-methylbenzamidefrom Example 204 (0.45 g, 1.16 mmol) was converted to the title compound(0.34 g, 62%), which was isolated as a yellow solid.

¹NMR; mp 179-182° C.; MS, m/e 441.0 (M+). Analysis for C₂₅H₃₃ClN₄O:Calcd: C, 68.09; H, 7.54; N, 12.70; Found: C, 67.81; H, 7.61; N, 12.76.

EXAMPLE 208 Preparation ofN-(5-Chloropyridin-2-yl)-2-[(1-cyclopentylpiperidin-4-yl)methylamino]-5-methylbenzamide

In a manner similar to that described in Example 206,N-(5-chloropyridin-2-yl)-2-[(4-piperidinylmethyl)amino]-5-methylbenzamidefrom Example 204 (0.45 g, 1.16 mmol) was converted to the title compound(0.28 g, 52%), which was isolated as a yellow solid.

¹NMR; mp 173-175° C.; MS, m/e 427.1 (M+). Analysis for C₂₄H₃₁ClN₄O:Calcd: C, 67.51; H, 7.32; N, 13.12; Found: C, 67.57; H, 7.33; N, 13.07.

EXAMPLE 209 Preparation ofN-(5-Chloropyridin-2-yl)-5-methyl-2-{[1-(tetrahydropyran-4-yl)piperidin-4-yl]methylamino}benzamide

In a manner similar to that described in Example 206,N-(5-chloropyridin-2-yl)-2-[(4-piperidinylmethyl)amino]-5-methylbenzamidefrom Example 204 (0.45 g, 1.16 mmol) was converted to the title compound(0.40 g, 73%), which was isolated as a yellow solid.

¹NMR; mp 178-182° C.; MS, m/e 443.2 (M+). Analysis for C₂₄H₃₁ClN₄O₂:Calcd: C, 65.07; H, 7.05; N, 12.65; Found: C, 64.43; H, 7.07; N, 12.27.

EXAMPLE 210 Preparation ofN-(5-Fluoropyridin-2-yl)-2-[(1-isopropylpiperidin-4-yl)methylamino]-5-methylbenzamide

A.N-(5-Fluoropyridin-2-yl)-5-methyl-2-[(4-piperidinylmethyl)amino]benzamide

In a manner similar to that described in Example 59,2-amino-N-(5-fluoropyridin-2-yl)-5-methylbenzamide (3.0 g, 12.2 mmol)was converted to the title compound (3.3 g, 78%), which was isolated asa yellow solid.

^(1,13)NMR, IR; mp 146.9-149.0° C.; LC-MS (method B): 98% pure,R_(t)=5.897 min, m/e 343.2 (M+1). Analysis for C₁₉H₂₃FN₄O.0.1CH₂Cl₂:Calcd: C, 65.38; H, 6.66; N, 15.96; Found: C, 65.74; H, 6.43; N, 15.79.

B.N-(5-Fluoropyridin-2-yl)-2-[(1-isopropylpiperidin-4-yl)methylamino]-5-methylbenzamide

In a manner similar to that described in Example 205,N-(5-fluoropyridin-2-yl)-5-methyl-2-[(4-piperidinylmethyl)amino]benzamidefrom Example 210-A (0.43 g, 1.24 mmol) was converted to the titlecompound (0.30 g, 63%), which was isolated as a yellow solid.

¹NMR; mp 58-60° C.; MS, m/e 385.1 (M+). Analysis for C₂₂H₂₉FN₄O.1.6H₂O:Calcd: C, 63.93; H, 7.85; N, 13.55; Found: C, 63.93; H, 7.79; N, 16.14.

EXAMPLE 211 Preparation of2-[(1-Butyrylpiperidin-4-yl)methylamino]-5-chloro-N-(5-chloropyridin-2-yl)benzamide

A small sample of5-chloro-N-(5-chloropyridin-2-yl)-2-[(4-piperidinylmethyl)amino]benzamidefrom Example 60 (60 mg, 0.16 mmol) was weighed out in a 4 mL sealablevial, followed by (piperidinomethyl)polystyrene (0.12 g, 0.32 mmol). Tothis was added 10 mL of amylene-stabilized chloroform and butyrylchloride (18.0 μL, 0.17 mmol). The vial was capped and placed in ashaker, where it was kept at room temperature for 24 h, then at 50° C.for 36 h. The crude reaction mixture was then applied to a 2 g SCXcolumn, washed with methanol and eluted with 1 N ammonia in methanol.The yellow fractions were combined and concentrated in vacuo to a dryresidue, which was purified by preparative thin layer chromatography.Elution with 9:1 dichloromethane-methanol provided the title compound (9mg, 13%), isolated in 98% purity by HPLC analysis (Method C: gradientfrom 50% acetonitrile-50% water with 0.1% trifluoroacetic acid to 90%acetonitrile-10% water with 0.1% trifluoroacetic acid over 10 min; hold2 min; back to 50% acetonitrile-10% water with 0.1% trifluoroacetic acidover 1 min; hold 2 min; 0.5 ml/min; Waters Symmetry Cl₁₈, 3.5 μM column,4.6 by 75 mm; 25° C.).

¹NMR; HPLC: 98% pure, R_(t)=9.967 min. MS, m/e 448.9 (M+).

EXAMPLE 212 Preparation of5-Chloro-N-(5-chloropyridin-2-yl)-2-[(1-isobutyrylpiperidin-4-yl)methylamino]benzamide

In a manner similar to that described in Example 211, a small sample of5-chloro-N-(5-chloropyridin-2-yl)-2-[(4-piperidinylmethyl)amino]benzamidefrom Example 60 (60 mg, 0.16 mmol) was converted to the title compound(23 mg, 33%), isolated in 99% purity by HPLC analysis (Method C,described in Example 211).

¹NMR; mp 99-101° C.; HPLC: 99% pure, R_(t)=9.836 min; MS, m/e 448.9(M+).

EXAMPLE 213 Preparation of5-Chloro-N-(5-chloropyridin-2-yl)-2-{[1-(thiophene-2-carbonyl)piperidin-4-yl]methylamino}benzamide

In a manner similar to that described in Example 211, a small sample of5-chloro-N-(5-chloropyridin-2-yl)-2-[(4-piperidinylmethyl)amino]benzamidefrom Example 60 (60 mg, 0.16 mmol) was converted to the title compound(38 mg, 49%), isolated in 99% purity by HPLC analysis (Method C,described in Example 211).

¹NMR; mp 163-165° C.; HPLC: 99% pure, R_(t)=10.542 min, m/e 488.9 (M+).Analysis for C₂₃H₂₂Cl₂N₄O₂S.1.0H₂O: Calcd: C, 54.44; H, 4.77; N, 11.04;Found: C, 54.87; H, 4.29; N, 10.72.

EXAMPLE 214 Preparation of5-Chloro-N-(5-chloropyridin-2-yl)-2-{[1-(morpholin-4-ylcarbonyl)piperidin-4-yl]methylamino}benzamide

In a manner similar to that described in Example 211, a small sample of5-chloro-N-(5-chloropyridin-2-yl)-2-[(4-piperidinylmethyl)amino]benzamidefrom Example 60 (60 mg, 0.16 mmol) was converted to the title compound(35 mg, 45%), isolated in 97% purity by HPLC analysis (Method C,described in Example 211).

¹NMR; mp 105-107° C.; HPLC: 97% pure, R_(t)=14.003 min. MS, m/e 491.9(M+). Analysis for C₂₃H₂₇Cl₂N₅O₃.0.5CH₂Cl₂: Calcd: C, 52.77; H, 5.28; N,13.09; Found: C, 52.71; H, 5.38; N, 12.68.

EXAMPLE 215 Preparation of5-Chloro-N-(5-chloropyridin-2-yl)-2-{[1-(3-methoxycarbonylpropionyl)piperidin-4-yl]methylamino}benzamide

In a manner similar to that described in Example 211, a small sample of5-chloro-N-(5-chloropyridin-2-yl)-2-[(4-piperidinylmethyl)amino]benzamidefrom Example 60 (60 mg, 0.16 mmol) was converted to the title compound(23 mg, 29%), isolated in 97% purity by HPLC analysis (Method D,gradient from 20% acetonitrile-80% water with 0.1% trifluoroacetic acidto 70% acetonitrile-30% water with 0.1% trifluoroacetic acid over 10min; hold 2 min; back to 20% acetonitrile-80% water with 0.1%trifluoroacetic acid over 1 min; hold 2 min; 0.5 mL/min; Waters SymmetryC₁₈ 3.5 μM column, 4.6 by 75 mm; 25° C.).

¹NMR; mp 71-74° C.; HPLC: 97% pure, R_(t)=12.692 min. MS, m/e 492.9(M+).

EXAMPLE 216 Preparation of5-Chloro-N-(5-chloropyridin-2-yl)-2-[(1-ethoxycarbonylmethylpiperidin-4-yl)methylamino]benzamide

A solution of5-chloro-N-(5-chloropyridin-2-yl)-2-[(4-piperidinylmethyl)amino]benzamidefrom Example 60 (0.5 g, 1.32 mmol)in 30 mL of dimethylformamide wastreated with excess ethyl bromoacetate (0.7 mL, 6.60 mmol). Afterheating at 70° C. for 1 h, triethylamine (0.9 ml, 6.6 mmol) was addeddropwise; the reaction mixture was then heated at 70° C. for anadditional 30 min, after which it was partitioned between saturatedsodium bicarbonate and dichloromethane. The organic extract wasconcentrated in vacuo, and the residue was applied to a 10 g SCX columnwhich was washed with methanol and eluted with 1 N ammonia in methanol.The yellow fractions were combined and concentrated in vacuo to affordan orange oil, which was subjected to silica gel chromatography. Elutionwith 9:1 dichloromethane-methanol, then 9:3 dichloromethane-methanolprovided 0.31 g (51%) of the title compound as a yellow solid.

¹NMR; mp 61-63° C.; MS, m/e 441.3 (M+). Analysis for C₂₂H₂₆Cl₂N₄O₃:Calcd: C, 56.78; H, 5.63; N, 12.04; Found: C, 56.86; H, 5.75; N, 12.23.

EXAMPLE 217 Preparation of2-(1-Carboxymethylpiperidin-4-yl)methylamino]-5-chloro-N-(5-chloropyridin-2-yl)benzamide

A solution of5-chloro-N-(5-chloropyridin-2-yl)-2-[(1-ethoxycarbonylmethylpiperidin-4-yl)methylamino]benzamidefrom Example 216 (1.5 g, 3.2 mmol) in 40 mL of 1:1 tetrahydrofuran-waterwas treated with sodium hydroxide (0.14 g, 3.50 mmol). After stirring atroom temperature for 24 h, the mixture was treated with 3.5 mL of 1 Nhydrochloric acid and concentrated in vacuo to remove thetetrahydrofuran. Filtration of the yellow solid formed uponconcentration provided the title amino acid (1.35 g, 95%) in 97% purityby HPLC analysis (Method D, described in Example 215).

¹NMR; mp 114-118° C.; HPLC: 97% pure, R_(t)=8.768 min. MS, m/e 436.9(M+).

EXAMPLE 218 Preparation of5-Chloro-N-(5-fluoropyridin-2-yl)-2-[4-piperidinylmethyl)amino]benzamide

In a manner similar to that described in Example 59,2-amino-5-chloro-N-(5-fluoropyridin-2-yl)benzamide (5 g, 19 mmol) wasconverted to the title compound (4.9 g, 71%), which was isolated as ayellow solid.

¹NMR; mp 243-246° C.; MS, m/e 362.9 (M+). Analysis forC₁₈H₂₀ClFN₄O.4.0H₂O: Calcd: C, 49.71; H, 6.49; N, 12.88; Found: C,49.23; H, 4.75; N, 13.65.

EXAMPLE 219 Preparation of5-Chloro-N-(5-fluoropyridin-2-yl)-2-[(1-isopropylpiperidin-4-yl)methylamino]benzamide

A solution of5-chloro-N-(5-fluoropyridin-2-yl)-2-[(4-piperidinylmethyl)amino]benzamidefrom Example 218 (0.50 g, 1.37 mmol) in 10 mL of acetone and 6 mL of95:5 methanol-acetic acid was treated with sodium cyanoborohydride (0.35g, 5.5 mmol). After stirring at 50° C. for 24 h, the solution wasconcentrated in vacuo; and the residue was subjected to silica gelchromatography. Elution with 98:2 dichloromethane-methanol furnished thetitle compound (0.12 g, 21%) as a yellow solid.

¹NMR; mp 72-74° C.; MS, m/e 405.0 (M+). Analysis forC₂₁H₂₆ClFN₄O.1.0H₂O: Calcd: C, 58.40; H, 6.77; N . 13.00; Found: C,58.22; H, 6.67; N, 14.91.

EXAMPLE 220 Preparation of5-Chloro-N-(5-chloropyridin-2-yl)-2-{[1-(3-methoxycarbonylpropyl)piperidin-4-yl]methylamino}benzamide

A small sample of5-chloro-N-(5-chloropyridin-2-yl)-2-[(4-piperidinylmethyl)amino]benzamidefrom Example 60 (60 mg, 0.16 mmol) was weighed out in a 4 mL sealablevial, followed by methyl 4-bromobutyrate (35 μL, 0.32 mmol). To this wasadded tetrahydrofuran (1.0 mL) and triethylamine (44 μL, 0.32 mmol). Thevial was capped and placed in a shaker where it was kept at 50° C. for36 h, after which the crude reaction mixture submitted to preparativethin layer chromatography. Elution with 19:1 dichloromethane-methanolprovided a tan residue (55 mg, 72%), which was identified as the titlecompound by LC-MS (Method A).

¹NMR; LC-MS: 99% pure, R_(t)=3.819 min, m/e 479.2 (M+).

EXAMPLE 221 Preparation of2-[(1-Acetylpiperidin-4-yl)methylamino]-5-chloro-N-(5-chloropyridin-2-yl)benzamide

A small sample of5-chloro-N-(5-chloropyridin-2-yl)-2-[(4-piperidinylmethyl)amino]benzamidefrom Example 60 (40 mg, 0.11 mmol) was weighed out in a 4 mL sealablevial, followed by addition of acetyl chloride (8 μL, 0.11 mmol),dichloromethane (500 μL) and triethylamine (15 μL, 0.11 mmol). The vialwas capped and placed in a shaker, where it was kept at room temperaturefor 48 h, followed by heating at 50° C. for 96 h. The crude reactionmixture was then submitted to preparative thin layer chromatography toafford a yellow residue (7 mg, 16%), which was identified as the titlecompound by LC-MS (Method A).

¹NMR; LC-MS: 97% pure, R_(t)=7.111 min, m/e 421.1 (M+).

EXAMPLE 222 Preparation of2-{[1-(3-Carboxypropyl)piperidin-4-yl]-methylamino}-5-chloro-N-(5-chloropyridin-2-yl)benzamide

A solution of5-chloro-N-(5-chloropyridin-2-yl)-2-{[1-(3-methoxycarbonylpropyl)piperidin-4-yl]methylamino}benzamidefrom Example 220 (32 mg, 0.067 mmol) in 1:1 water-tetrahydrofuran (400μL) was treated with 1 N aqueous sodium hydroxide (73 μL, 0.073 mmol).The vial was capped and placed in a shaker, heated at 50° C. for 24 h.The crude reaction mixture was directly submitted to preparative thinlayer chromatography. Elution with 19:1 dichloromethane-2 M ammonia inmethanol furnished a yellow residue (17 mg, 56%), which was identifiedas the title compound by LC-MS (Method A).

LC-MS: 99% pure, R_(t)=2.891 min, m/e 465.1 (M+).

EXAMPLE 223 Preparation of5-Chloro-N-(5-chloropyridin-2-yl)-2-{[1-(2-cyano-1-methylethyl)piperidin-4-yl]methylamino}benzamide

To a sample of5-chloro-N-(5-chloropyridin-2-yl)-2-[(4-piperidinylmethyl)amino]benzamidefrom Example 60 (32 mg, 0.067 mmol) in a 4 mL sealable glass vial, wasadded crotonitrile (26 μL, 0.32 mmol), tetraethyl orthosilicate (70 μL,0.32 mmol), cesium fluoride (2 mg, 0.016 mmol), andN-methylpyrrolidinone (500 μL). The vial was capped and placed in ashaker, heated at 70° C. for 72 h. The reaction mixture was concentratedin vacuo, and the residue was subjected to silica gel chromatography.Elution with 9:1 dichloromethane-methanol provided a yellow solid (9 mg,12%), which was identified as the title compound by LC-MS (Method A).

LC-MS: 97% pure, R_(t)=3.272 min, m/e 446.1 (M+).

EXAMPLE 224 Preparation of5-Chloro-N-(5-chloropyridin-2-yl)-2-{[1-(2-methoxycarbonyl-1-methylethyl)piperidin-4-yl]methylamino}benzamide

In a manner similar to that described in Example 223,5-chloro-N-(5-chloropyridin-2-yl)-2-[(4-piperidinylmethyl)amino]benzamidefrom Example 60 (32 mg, 0.067 mol) was converted to the title compound(7 mg, 9%), which was isolated as a yellow film in 98% purity by HPLCanalysis (Method C, described in Example 211).

HPLC: 98% pure, R_(t)=8.024 min.; MS, m/e 477.9 (M+).

EXAMPLE 225 Preparation of5-Chloro-N-(5-chloropyridin-2-yl)-2-{[1-(2-carbamoylethyl)piperidin-4-yl]methylamino}benzamide

In a manner similar to that described in Example 223,5-chloro-N-(5-chloropyridin-2-yl)-2-[(4-piperidinylmethyl)amino]benzamidefrom Example 60 (60 mg, 0.16 mmol) was converted to the title compound(35 mg, 49%), which was isolated as a yellow solid and identified byLC-MS analysis (Method A).

mp 193-196° C.; LC-MS: 99% pure, R_(t)=2.289 min, m/e 450.1 (M+).

EXAMPLE 226 Preparation of2-{[1-(2-Carboxyethyl)piperidin-4-yl]methylamino}-5-chloro-N-(5-chloropyridin-2-yl)benzamide

In a manner similar to that described in Example 223,5-chloro-N-(5-chloropyridin-2-yl)-2-[(4-piperidinylmethyl)amino]benzamidefrom Example 60 (60 mg, 0.16 mmol) was converted to the title compound(32 mg, 45%), which was isolated as a tan film and identified by LC-MSanalysis (Method A).

LC-MS: 99% pure, R_(t)=2.755 min, m/e 451.1 (M+).

EXAMPLE 227 Preparation ofN-(5-Chloropyridin-2-yl)-2-[(1-isopropylpiperidin-4-yl)methylamino]-5-methylsulfonylaminobenzamide

A.N-(5-Chloropyridin-2-yl)-2-[(4-piperidinyl)methylamino]-5-methanesulfonylaminobenzamide

A suspension of5-amino-N-(5-chloropyridin-2-yl)-2-[(1-Boc-piperidin-4-yl)methylamino]benzamide(0.55 g, 1.2 mmol) in 12 mL of dichloromethane at 0° C. was treated withethyldiisopropylamine (231 μL, 1.3 mmol) followed by methanesulfonylchloride (93 μL, 1.2 mmol). The reaction mixture was allowed to reachroom temperature overnight, then it was concentrated in vacuo to a cruderesidue. The residue was directly applied to an SCX column, which waswashed with methanol and allowed to stand overnight. Elution with 1:1dichloromethane-1 N ammonia in methanol provided yellow fractions, whichwere combined and concentrated in vacuo to a crude residue. Purificationby silica gel chromatography, eluting with 9:1 dichloromethane-2 Nammonia in methanol, afforded solid material which was taken up inacetonitrile and sonicated for several minutes. The resulting suspensionwas filtered, giving rise to the title compound (0.29 g, 56%) as apale-yellow solid.

¹NMR, IR; mp 222.8-226.0° C.; MS, m/e 438.2 (M+). Analysis forC₂₂H₃₀ClN₅O₃S: Calcd: C, 52.11; H, 5.52; N, 15.99; Found: C, 52.16; H,5.39; N, 15.96.

B.N-(5-Chloropyridin-2-yl)-2-[(1-isopropylpiperidin-4-yl)methylamino]-5-methanesulfonylaminobenzamide

In a manner similar to that described in Example 205,N-(5-chloropyridin-2-yl)-2-[(piperidin-4-yl)methylamino]-5-methanesulfonylaminobenzamidefrom Example 227-A (0.29 g, 0.67 mmol) was converted to the titlecompound (0.29 g, 91%), which was isolated as a pale-yellow solid.

¹NMR, IR; mp 203.7-205.4° C.; MS, m/e 480.2 (M+). Analysis forC₂₂H₃₀ClN₅O₃S: Calcd: C, 55.05; H, 6.30; N, 14.59; Found: C, 54.84; H,6.20; N, 14.66.

EXAMPLE 228 Preparation of5-Chloro-N-(5-chloropyridin-2-yl)-2-{[1-(2-methoxycarbonylethyl)piperidin-4-yl]methylamino}benzamide

In a manner similar to that described in Example 223,5-chloro-N-(5-chloropyridin-2-yl)-2-[(4-piperidinylmethyl)amino]benzamidefrom Example 60 (60 mg, 0.16 mmol) was converted to the title compound(41 mg, 55%), which was isolated as a yellow residue of 98% purity byHPLC analysis (Method D, described in Example 215).

HPLC: 98% pure, R_(t)=9.425 min.; MS, m/e 464.8 (M+).

EXAMPLE 229 Preparation of5-Chloro-N-(5-chloropyridin-2-yl)-2-{[1-(2-cyanoethyl)piperidin-4-yl]methylamino}benzamide

In a manner similar to that described in Example 223,5-chloro-N-(5-chloropyridin-2-yl)-2-[(4-piperidinylmethyl)amino]benzamidefrom Example 60 (60 mg, 0.16 mmol) was converted to the title compound(64 mg, 94%), which was isolated as a yellow residue of 98% purity byHPLC analysis (Method D, described in Example 215).

HPLC: 98% pure, R_(t)=9.127 min.; MS, m/e 431.9 (M+)

EXAMPLE 230 Preparation of2-[(4-tert-Butylpiperazin-1-ylcarbonyl)amino]-N-(5-chloropyridin-2-yl)benzamide

A. 3-(2-Hydroxyethyl)oxazolidin-2-one

A mixture of diethanolamine (12.55 g), diethyl carbonate (16.2 mL), andsodium methoxide (80 mg) was heated to 130-140° C. for 1.5 h anddistilled during the reaction using a Dean-Stark trap. The remainingliquid was concentrated in vacuo to give 15.11 g (97%) as a yellow oil.

¹H NMR.

B. 3-[2-(4-Toluenesulfonyloxy)ethyl]oxazolidin-2-one

To an ice cold stirring solution of crude3-(2-hydroxyethyl)oxazolidin-2-one (15.1 g, 115 mmol) in dichloromethane(40 mL) was added triethylamine (18 mL, 129 mmol), and4-(N,N-dimethylamino)pyridine (0.143 g, 1.2 mmol). A slurry of4-toluenesulfonyl chloride (25.0 g, 131 mmol) in dichloromethane (50 mL)was then added dropwise. The reaction mixture was stirred for 3 d atroom temperature, washed with saturated aqueous sodium bicarbonate,dried over magnesium sulfate, filtered, and concentrated in vacuo. Theresidue was slurried in isopropanol and filtered to give 23.88 g (73%)of a white solid.

IS-MS, m/e 286.0 (m+1).

C. 3-[2-(tert-Butylamino)]ethyl]oxazolidin-2-one

To a mixture of 3-[2-(4-toluenesulfonyloxy)ethyl]oxazolidin-2-one (2.01g, 7.04 mmol) and potassium carbonate (0.99 g, 7.2 mmol) in acetonitrile(19 mL) was added tert-butylamine (15 mL). The mixture was heated atreflux for 4 h, and partitioned between dichloromethane and water. Theorganic phase was dried over magnesium sulfate, filtered, andconcentrated in vacuo to give 1.18 g (91%) of a yellow oil.

¹H NMR; IS-MS, m/e 187.1 (m+1).

D. 1-tert-Butylpiperazine Dihydrobromide

To crude 3-[2-(tert-butylamino)ethyl]oxazolidin-2-one (1.18 g, 6.33mmol) was added acetic acid (8.8 mL) and then 45% hydrobromic acid inacetic acid (19.5 mL). The reaction solution was stirred at roomtemperature for 3 d, poured into dichloromethane (250 mL), and filteredto give 1.87 g of a brown solid. The solid was heated at reflux inn-butanol for 2 d and the reaction mixture concentrated in vacuo. Theresidual solid was slurried in 3:1 diethyl ether:dichloromethane andfiltered. The filtered solid was heated in ethanol, cooled to roomtemperature, and filtered to give 0.57 g (30%) of a white solid.

¹H NMR; IS-MS, m/e 143.1 (m+1); Analysis for C₈H₁₈N₂O₄.2HBr: Calcd: C;24.89; H, 5.74; N, 7.26; Br, 41.40; Found: C, 31.88; H, 6.53; N, 9.16;Br, 52.22.

E. Methyl 2-[(4-tert-Butylpiperazin-1-ylcarbonyl)amino]benzoate

To an ice cold solution of methyl 2-isocyanatobenzoate (0.18 g, 1.0mmol) in dichloromethane (3 mL) was added dropwise a solution of1-tert-butylpiperazine dihydrobromide (0.28 g, 0.92 mmol) andN,N-diisopropylethylamine (0.36 mL, 2.1 mmol) in N,N-dimethylformamide(5 mL). The reaction solution was stirred at room temperature for 1 h,diluted with ethyl acetate, washed with saturated aqueous sodiumbicarbonate, dried over magnesium sulfate, filtered, and concentrated invacuo to give 0.28 g (95%) of a yellow oil.

¹H NMR; IS-MS, m/e 320.2 (m+1); Analysis for C₁₇H₂₅N₃O₃: Calcd: C,63.93; H, 7.89; N, 13.16; Found: C, 62.79; H, 7.73; N, 13.07.

F. 2-[(4-tert-Butylpiperazin-1-ylcarbonyl)amino]benzoic AcidHydrochloride

To an ice cold solution of methyl2-[(4-tert-butylpiperazin-1-ylcarbonyl)amino]benzoate (0.24 g, 0.75mmol) in tetrahydrofuran (12 mL) and water (3 mL) was added dropwise 1 Naqueous lithium hydroxide (0.95 mL, 0.95 mmol). The reaction solutionwas stirred at room temperature for 22 h, concentrated in vacuo, and theresidue partitioned between water and diethyl ether. The aqueous phasewas acidified to pH 2 using 1 N hydrochloric acid and lyophilized togive 0.25 g of crude material as a white solid.

¹H NMR; IS-MS, m/e 306.1 (m+1), 304.2 (m−1).

G. 2-(4-tert-Butylpiperazin-1-yl)-4H-3,1-benzoxazin-4-one

Using methods substantially equivalent to those described in Example51-C, 2-(4-tert-butylpiperazin-1-yl)-4H-3,1-benzoxazin-4-one (0.13 g,75%) was prepared from2-[(4-tert-butylpiperazin-1-ylcarbonyl)amino]benzoic acid hydrochloride(0.22 g, 0.6 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimidehydrochloride in the presence of N,N-diisopropylethylamine (0.14 mL, 0.8mmol).

¹H NMR; IS-MS, m/e 288.1 (m+1).

H.2-[(4-tert-Butylpiperazin-1-ylcarbonyl)amino]-N-(5-chloropyridin-2-yl)benzamide

Using methods substantially equivalent to those described in Example51-D,2-[(4-tert-butylpiperazin-1-ylcarbonyl)amino]-N-(5-chloropyridin-2-yl)benzamide(62 mg, 33%) was prepared from2-[(4-tert-butylpiperazin-1-yl)-4H-3,1-benzoxazin-4-one (0.13 g, 0.45mmol) and 2-amino-5-chloropyridine. The crude product was suspended inether and filtered.

¹H NMR; IS-MS, m/e 416.1(m+1), 471.3 (m−1); Analysis forC₂₁H₂₆ClN₅O₂.0.5H₂O: Calcd: C, 59.36; H, 6.40; N, 16.48; Found: C,59.09; H, 6.12; N, 16.09.

EXAMPLE 231 Preparation ofN-(5-Chloropyridin-2-yl)-2-[(1-isopropylpiperidin-4-ylcarbonyl)amino]-5-methylbenzamideHydrochloride

A. N-(5-Chloropyridin-2-yl)-5-methyl-2-nitrobenzamide

To a stirring suspension of 5-methyl-2-nitrobenzoic acid (23.36 g, 129mmol) in dichloromethane (100 mL) was added a couple of drops ofN,N-dimethylformamide followed by oxalyl chloride (12.36 mL, 142 mmol).The reaction was stirred at room temperature overnight and the residuetransferred slowly to an ice cold solution of 2-amino-5-chloropyridine(16 g, 126 mmol) and pyridine (30 mL) in dichloromethane (200 mL). Thereaction was stirred overnight, treated with water (100 mL), andconcentrated. The resulting mixture was treated with ethyl acetate (2L), washed consecutively with aqueous citric acid, saturated aqueoussodium bicarbonate, dried over magnesium sulfate, filtered, andconcentrated in vacuo. The crude product was purified byrecrystallization from toluene to give 26 g (69%) of a white solid.

¹H NMR; ESI+MS, m/e 292.0 (m+1); Analysis for C₁₃H₁₀ClN₃O₃: Calcd: C,53.53; H, 3.46; N, 14.41; Found: C, 53.52; H, 3.56; N, 14.49.

B. 2-Amino-N-(5-chloropyridin-2-yl)-5-methylbenzamide.

Using methods substantially equivalent to those described in Example2-B, 2-amino-5-methyl-N-(5-chloropyridin-2-yl)benzamide (19 g, 88%) wasprepared from N-(5-chloropyridin-2-yl)-5-methyl-2-nitrobenzamide.

¹H NMR; ESI+MS, m/e 262.0 (m+1); Analysis for C₁₃H₁₂ClN₃O: Calcd: C,59.66; H, 4.62; N, 16.06; Found: C, 64.32; H, 4.81; N, 17.59.

C.2-[(1-tert-Butoxycarbonylpiperidin-4-ylcarbonyl)amino]-N-(5-chloropyridin-2-yl)-5-methylbenzamide.

Using methods substantially equivalent to those described in Example25-D,2-[(1-tert-butoxycarbonylpiperidin-4-ylcarbonyl)amino]-N-(5-chloropyridin-2-yl)-5-methylbenzamide(4.3 g, 79%) was prepared from2-amino-N-(5-chloropyridin-2-yl)-5-methylbenzamide.

¹H NMR; IS-MS, m/e 473.2 (m+1), 471.3 (m−1); Analysis for C₂₄H₂₉ClN₄O₄:Calcd: C, 60.95; H, 6.18; N, 11.85; Found: C, 61.17; H, 6.41; N, 11.90.

D.N-(5-Chloropyridin-2-yl)-5-methyl-2-[(4-piperidinylcarbonyl)amino]benzamideTrifluoroacetate.

Using methods substantially equivalent to those described in Example9-B,N-(5-chloropyridin-2-yl)-2-[(4-piperidinylcarbonyl)amino]-5-methylbenzamidetrifluoroacetate (4.7 g, 100%) was prepared from2-[(1-tert-butoxycarbonylpiperidin-4-ylcarbonyl)amino]-N-(5-chloropyridin-2-yl)-5-methylbenzamide.

¹H NMR; IS-MS, m/e 373.2 (m+1), 371.1 (m−1); Analysis forC₁₉H₂₀ClN₄O₂.1.6C₂HF₃O₂: Calcd: C, 48.02; H, 4.10; N, 10.09; F, 16.42;Found: C, 48.34; H, 3.98; N, 10.06; F, 17.50.

E.N-(5-Chloropyridin-2-yl)-2-[(1-isopropylpiperidin-4-ylcarbonyl)amino]-5-methylbenzamideHydrochloride.

To a stirring suspension ofN-(5-chloropyridin-2-yl)-5-methyl-2-[(4-piperidinylcarbonyl)amino]benzamidetrifluoroacetate (1.0 g, 2.05 mmol) in methanol (30 mL) was addedacetone (15 mL), followed by acetic acid (0.6 mL, 10.5 mmol), and thensodium cyanoborohydride (0.165 g, 2.46 mmol). After stirring overnight,the solution was treated with saturated aqueous ammonium chloridesolution, concentrated, and partitioned between dichloromethane andsaturated aqueous sodium bicarbonate. The organic phase was washed withbrine, dried over magnesium sulfate, filtered, and concentrated. Thecrude product was purified by chromatography over silica gel, elutingwith a step gradient of 0-10% 2 M solution of ammonia/methanol indichloromethane. To a stirring solution of the chromatography product indichloromethane was added 1.0 N hydrochloric acid in diethyl ether untilprecipitate formed. The mixture was filtered to give 0.81 g (88%) of awhite solid.

¹H NMR; IS-MS, m/e 415.2 (m+1), 413.2 (m−1); Analysis forC₂₂H₂₇ClN₄O₂.2.0HCl.0.1H₂O: Calcd: C, 53.96; H, 6.01; N, 11.44; Cl,21.72; Found: C, 54.09; H, 6.00; N, 11.39; Cl, 21.75.

EXAMPLE 232 Preparation of2-[(4-tert-Butylpiperazin-1-ylcarbonyl)amino]-5-chloro-N-(5-chloropyridin-2-yl)benzamideHydrochloride

A. 4-Chloro-2-iodoaniline.

Using methods substantially equivalent to those described in Example173-C, 4-chloro-2-iodoaniline (50.92 g, 51%) was prepared from4-chloroaniline.

¹H NMR; EI-MS, m/e 252.9 (m); Analysis for C₆H₅ClIN: Calcd: C, 28.43; H,1.99; N, 5.53; Found: C, 28.35; H, 2.02; N, 5.52.

B. 2-[(4-tert-Butylpiperazin-1-ylcarbonyl)amino]-5-chloro-1-iodobenzene.

To a stirring solution of triphosgene (0.35 g, 1.16 mmol) indichloromethane (12 mL) was added dropwise a solution of4-chloro-2-iodoaniline (0.80 g, 3.15 mmol). The reaction mixture wasstirred for 30 min. Then, using methods substantially equivalent tothose described in Example 230-E,2-[(4-tert-butylpiperazin-1-ylcarbonyl)amino]-5-chloro-1-iodobenzene wasprepared from 1-tert-butylpiperazine dihydrobromide (1.03 g, 3.4 mmol).

¹H NMR; IS-MS, m/e 421.9 (m+1), 420.0 (m−1); Analysis for C₁₅H₂₁ClIN₃O:Calcd: C, 42.72; H, 5.01; N, 9.97; Found: C, 42.16; H, 5.11; N, 9.60.

C. 2-(4-tert-Butylpiperazin-1-yl)-6-chloro-4H-3,1-benzoxazin-4-one.

Using methods substantially equivalent to those described in Example173-D, crude2-(4-tert-butylpiperazin-1-yl)-6-chloro-4H-3,1-benzoxazin-4-one (0.49 g)was prepared from2-[(4-tert-butylpiperazin-1-ylcarbonyl)amino]-5-chloro-1-iodobenzene.

¹H NMR; IS-MS, m/e 322.0 (m+1).

D.2-[(4-tert-Butylpiperazin-1-ylcarbonyl)amino]-5-chloro-N-(5-chloropyridin-2-yl)benzamideHydrochloride.

Using methods substantially equivalent to those described in Example51-D,2-[(4-tert-butylpiperazin-1-ylcarbonyl)amino]-5-chloro-N-(5-chloropyridin-2-yl)benzamidehydrochloride (0.15 g, 44%) was prepared from2-(4-tert-butylpiperazin-1-yl)-6-chloro-4H-3,1-benzoxazin-4-one (0.49 g,0.8 mmol) and 2-amino-5-chloropyridine. The product was purified withreverse phase HPLC, eluting with a gradient from 20% through 60%acetonitrile in 0.05% aqueous hydrochloric acid.

¹H NMR; IS-MS, m/e 448.1 (m−1); Analysis forC₂₁H₂₅Cl₂N₅O₂.2.0HCl.0.5H₂O: Calcd: C, 47.38; H, 5.30; N, 13.16; Cl,26.64; Found: C, 47.45; H, 4.91; N, 12.76; Cl, 25.44.

EXAMPLE 233 Preparation ofN-(5-Chloropyridin-2-yl)-2-[(1-isopropylpiperidin-4-ylcarbonyl)amino]-3-methylbenzamideHydrochloride

A. N-(5-Chloropyridin-2-yl)-3-methyl-2-nitrobenzamide.

Using methods substantially equivalent to those described in Example231-A, N-(5-chloropyridin-2-yl)-3-methyl-2-nitrobenzamide (36 g, 74%)was prepared from 3-methyl-2-nitrobenzoic acid.

¹H NMR; ESI+MS, m/e 292.0 (m+1); Analysis for C₁₃H₁₀ClN₃O₃: Calcd: C,53.53; H, 3.46; N, 14.41; Found: C, 53.49; H, 3.40; N, 14.30.

B. 2-Amino-N-(5-chloropyridin-2-yl)-3-methylbenzamide.

Using methods substantially equivalent to those described in Example2-B, 2-amino-N-(5-chloropyridin-2-yl)-3-methylbenzamide (36 g, 95%) wasprepared from N-(5-chloropyridin-2-yl)-3-methyl-2-nitrobenzamide.

¹H NMR; ES-MS, m/e 262.0 (m+1); Analysis for C₁₃H₁₂ClN₃O: Calcd: C,59.66; H, 4.62; N, 16.06; Found: C, 59.24; H, 4.28; N, 16.08.

C.2-[(1-tert-Butoxycarbonylpiperidin-4-ylcarbonyl)amino]-N-(5-chloropyridin-2-yl)-3-methylbenzamide.

Using methods substantially equivalent to those described in Example25-D,2-[(1-tert-butoxycarbonylpiperidin-4-ylcarbonyl)amino]-N-(5-chloropyridin-2-yl)-3-methylbenzamide(3.82 g, 70%) was prepared from2-amino-N-(5-chloropyridin-2-yl)-3-methylbenzamide.

¹H NMR; IS-MS, m/e 473.2 (m+1), 471.3 (m−1); Analysis for C₂₄H₂₉ClN₄O₄:Calcd: C, 60.95; H, 6.18; N, 11.85; Found: C, 60.71; H, 6.04; N, 11.74.

D.N-(5-Chloropyridin-2-yl)-3-methyl-2-[(4-piperidinylcarbonyl)amino]benzamideTrifluoroacetate.

Using methods substantially equivalent to those described in Example9-B,N-(5-chloropyridin-2-yl)-3-methyl-2-[(4-piperidinylcarbonyl)amino]benzamidetrifluoroacetate (3.15 g, >100% probably due to >1 eq TFA), was preparedfrom2-[(1-tert-butoxycarbonylpiperidin-4-ylcarbonyl)amino]-N-(5-chloropyridin-2-yl)-3-methylbenzamide.

¹H NMR;

E.N-(5-Chloropyridin-2-yl)-2-[(1-isopropylpiperidin-4-ylcarbonyl)amino]-3-methylbenzamideHydrochloride.

Using methods substantially equivalent to those described in Example231-E,N-(5-chloropyridin-2-yl)-2-[(1-isopropylpiperidin-4-ylcarbonyl)amino]-3-methylbenzamidehydrochloride (0.49 g, 53%) was prepared fromN-(5-chloropyridin-2-yl)-3-methyl-2-[(piperidin-4-ylcarbonyl)amino]benzamidetrifluoroacetate.

¹H NMR; IS-MS, m/e 415.2 (m+1), 413.2 (m−1); Analysis forC₂₂H₂₇ClN₄O₂.1.1HCl.0.2H₂O: Calcd: C, 57.61; H, 6.26; N, 12.22; Cl,16.23; Found: C, 57.42; H, 6.18; N, 12.01; Cl, 16.13.

EXAMPLE 234 Preparation ofN-(5-Chloropyridin-2-yl)-2-[(1-isopropylpiperidin-4-ylcarbonyl)amino]-5-methoxybenzamideHydrochloride

A. N-(5-Chloropyridin-2-yl)-5-methoxy-2-nitrobenzamide.

Using methods substantially equivalent to those described in Example231-A, N-(5-chloropyridin-2-yl)-5-methoxy-2-nitrobenzamide (26.5 g, 62%)was prepared from 5-methoxy-2-nitrobenzoic acid.

¹H NMR; ESI+MS, m/e 308.0 (m+1); Analysis for C₁₃H₁₀ClN₃O₄: Calcd: C,50.75; H, 3.28; N, 13.66; Found: C, 50.80; H, 3.15; N, 13.89.

B. 2-Amino-N-(5-chloropyridin-2-yl)-5-methoxybenzamide.

Using methods substantially equivalent to those described in Example2-B, 2-amino-N-(5-chloropyridin-2-yl)-5-methoxybenzamide (20 g, 84%) wasprepared from N-(5-chloropyridin-2-yl)-5-methoxy-2-nitrobenzamide.

¹H NMR; ESI+MS, m/e 278.1 (m+1); Analysis for C₁₃H₁₂ClN₃O₂: Calcd: C,56.23; H, 4.36; N, 15.13; Found: C, 56.34; H, 4.32; N, 14.92.

C.2-[(1-tert-Butoxycarbonylpiperidin-4-ylcarbonyl)amino]-N-(5-chloropyridin-2-yl)-5-methoxybenzamide.

Using methods substantially equivalent to those described in Example25-D,2-[(1-tert-butoxycarbonylpiperidin-4-ylcarbonyl)amino]-N-(5-chloropyridin-2-yl)-5-methoxybenzamide(1.59 g, 90%) was prepared from2-amino-N-(5-chloropyridin-2-yl)-5-methoxybenzamide.

¹H NMR; IS-MS, m/e 489.5 (m+1), 487.5 (m−1); Analysis for C₂₄H₂₉ClN₄O₅:Calcd: C, 58.95; H, 5.98; N, 11.46; Found: C, 59.10; H, 5.98; N, 11.32.

D.N-(5-Chloropyridin-2-yl)-5-methoxy-2-[(4-piperidinylcarbonyl)amino]benzamideTrifluoroacetate.

Using methods substantially equivalent to those described in Example9-B,N-(5-chloropyridin-2-yl)-5-methoxy-2-[(4-piperidinylcarbonyl)amino]benzamidetrifluoroacetate (1.14 g, 93%) was prepared from2-[(1-tert-butoxycarbonylpiperidin-4-ylcarbonyl)amino]-N-(5-chloropyridin-2-yl)-5-methoxybenzamide.

¹H NMR; IS-MS, m/e 389.3 (m+1), 387.2 (m−1); Analysis forC₁₉H₂₁ClN₄O₃.1.0C₂HF₃O₂: Calcd: C, 50.16; H, 4.41; N, 11.14; F, 11.33;Found: C, 49.88; H, 4.49; N, 10.86; F, 11.52.

E.N-(5-Chloropyridin-2-yl)-2-[(1-isopropylpiperidin-4-ylcarbonyl)amino]-5-methoxybenzamideHydrochloride.

Using methods substantially equivalent to those described in Example231-E,N-(5-chloropyridin-2-yl)-2-[(1-isopropylpiperidin-4-ylcarbonyl)amino]-5-methoxybenzamidehydrochloride (0.36 g, 39%) was prepared fromN-(5-chloropyridin-2-yl)-5-methoxy-2-[(piperidin-4-ylcarbonyl)amino]benzamidetrifluoroacetate.

¹H NMR; IS-MS, m/e 431.4 (m+1), 429.3 (m−1); Analysis forC₂₂H₂₇ClN₄O₃.1.0HCl: Calcd: C, 56.54; H, 6.04; N, 11.99; Cl, 15.17;Found: C, 56.56; H, 5.77; N, 11.78; Cl, 15.46.

EXAMPLE 235 Preparation of3-Chloro-N-(5-chloropyridin-2-yl)-2-[(1-isopropylpiperidin-4-ylcarbonyl)amino]benzamideHydrochloride

A. 3-Chloro-N-(5-chloropyridin-2-yl)-2-nitrobenzamide.

Using methods substantially equivalent to those described in Example231-A, 3-chloro-N-(5-chloropyridin-2-yl)-2-nitrobenzamide (4.11 g, 37%)was prepared from 3-chloro-2-nitrobenzoic acid.

¹H NMR; IS-MS, m/e 312.0 (m+1), 310.1 (m−1); Analysis for C₁₂H₇Cl₂N₃O₃:Calcd: C, 46.18; H, 2.26; N, 13.46; Found: C, 46.05; H, 2.19; N, 13.54.

B. 2-Amino-3-chloro-N-(5-chloropyridin-2-yl)benzamide.

Using methods substantially equivalent to those described in Example2-B, 2-amino-3-chloro-N-(5-chloropyridin-2-yl)benzamide (2.97 g, 84%)was prepared from 3-chloro-N-(5-chloropyridin-2-yl)-2-nitrobenzamide.

¹H NMR; IS-MS, m/e 282.1 (m+1), 280.1 (m−1); Analysis for C₁₂H₉Cl₂N₃O:Calcd: C, 51.09; H, 3.22; N, 14.89; Found: C, 50.80; H, 3.22; N, 14.66.

C.2-[(1-tert-Butoxycarbonylpiperidin-4-ylcarbonyl)amino]-3-chloro-N-(5-chloropyridin-2-yl)benzamide.

Using methods substantially equivalent to those described in Example25-D,2-[(1-tert-butoxycarbonylpiperidin-4-ylcarbonyl)amino]-3-chloro-N-(5-chloropyridin-2-yl)benzamide(0.31 g, 18%) was prepared from2-amino-3-chloro-N-(5-chloropyridin-2-yl)benzamide.

¹H NMR; IS-MS, m/e 493.0 (m+1), 491.2 (m−1); Analysis for C₂₃H₂₆Cl₂N₄O₄:Calcd: C, 55.99; H, 5.31; N, 11.36; Found: C, 56.14; H, 5.58; N, 11.23.

D.3-Chloro-N-(5-chloropyridin-2-yl)-2-[(4-piperidinylcarbonyl)amino]benzamideTrifluoroacetate.

Using methods substantially equivalent to those described in Example9-B,3-chloro-N-(5-chloropyridin-2-yl)-2-[(4-piperidinylcarbonyl)amino]benzamidetrifluoroacetate (0.20 g, 100%) was prepared from2-[(1-tert-butoxycarbonylpiperidin-4-ylcarbonyl)amino]-3-chloro-N-(5-chloro-pyridin-2-yl)benzamide.

¹H NMR; IS-MS, m/e 393.1 (m+1), 391.2 (m−1); Analysis forC₁₈H₁₈Cl₂N₄O₂.1.0C₂HF₃O₂: Calcd: C, 47.35; H, 3.78; N, 11.04; F, 11.24;Found: C, 47.62; H, 3.87; N, 10.89; F, 11.53.

E.3-Chloro-N-(5-chloropyridin-2-yl)-2-[(1-isopropylpiperidin-4-ylcarbonyl)amino]benzamideHydrochloride.

Using methods substantially equivalent to those described in Example231-E,3-chloro-N-(5-chloropyridin-2-yl)-2-[(1-isopropylpiperidin-4-ylcarbonyl)amino]benzamidehydrochloride (71 mg, 50%) was prepared from3-chloro-N-(5-chloropyridin-2-yl)-2-[(4-piperidinylcarbonyl)amino]-benzamidetrifluoroacetate.

¹H NMR; IS-MS, m/e 435.2 (m+1), 433.4 (m−1); Analysis forC₂₁H₂₄Cl₂N₄O₁.1.2HCl.0.1H₂O: Calcd: C, 52.45; H, 5.32; N, 11.65; Cl,23.59; Found: C, 52.67; H, 5.11; N, 11.42; Cl, 23.81.

EXAMPLE 236 Preparation of5-Chloro-N-(6-chloropyridazin-3-yl)-2-[(1-isopropylpiperidin-4-ylcarbonyl)amino]benzamideHydrochloride

A.2-[(1-tert-Butoxycarbonylpiperidin-4-ylcarbonyl)amino]-5-chloro-1-iodobenzene.

Using methods substantially equivalent to those described in Example25-D,2-[(1-tert-butoxycarbonylpiperidin-4-ylcarbonyl)amino]-5-chloro-1-iodobenzene(14.04 g, 94%) was prepared from 4-chloro-2-iodoaniline.

¹H NMR;

IS-MS, m/e 465.1 (m+1), 463.2 (m−1);

Analysis for C₁₇H₂₂ClIN₂O₃: Calcd: C, 43.94; H, 4.77; N, 6.03; Found: C,45.40; H, 5.14; N, 5.98.

B.2-[(1-tert-Butoxycarbonylpiperidin-4-ylcarbonyl)amino]-5-chlorobenzoicAcid.

To a stirring solution of2-[(1-tert-butoxycarbonylpiperidin-4-ylcarbonyl)amino]-5-chloro-1-iodobenzene(10 g, 21.5 mmol) in acetonitrile (350 mL) was added potassium carbonate(14.9 g, 107.5 mmol), followed by Pd(PPh₃)₄ (1.24 g, 1.1 mmol), andcopper iodide (0.21 g, 1.1 mmol). The mixture was placed under anatmosphere of carbon monoxide and heated to 80° C. After 3 h, 1 Naqueous sodium hydroxide (50 mL) was added to the hot reaction solution.The solution was stirred for 10 min and concentrated in vacuo. Theresidue was partitioned between ethyl acetate and water. The aqueousphase was filtered, acidified to pH 3 with citric acid, and extractedwith ethyl acetate The organic phase was washed with brine, dried overmagnesium sulfate, filtered, and concentrated in vacuo to give 3.91 g(48%) of a white solid.

¹H NMR;

C.2-(1-tert-Butoxycarbonylpiperidin-4-yl)-6-chloro-4H-3,1-benzoxazin-4-one.

Using methods substantially equivalent to those described in Example51-C,2-[(1-tert-butoxycarbonylpiperidin-4-yl)-6-chloro-4H-3,1-benzoxazin-4-one(2.5 g, 75%) was prepared from2-[(1-tert-butoxycarbonylpiperidin-4-ylcarbonyl)amino]-5-chlorobenzoicacid.

¹H NMR;

D.2-[(1-tert-Butoxycarbonylpiperidin-4-ylcarbonyl)amino]-5-chloro-N-(6-chloropyridazin-3-yl)benzamide.

Using methods substantially equivalent to those described in Example51-D,2-[(1-tert-butoxycarbonylpiperidin-4-ylcarbonyl)amino]-5-chloro-N-(6-chloropyridazin-3-yl)benzamide(0.65 g, 26%) was prepared from2-(1-tert-butoxycarbonylpiperidin-4-yl)-6-chloro-4H-3,1-benzoxazin-4-one(0.93 g, 2.55 mmol) and 3-amino-6-chloropyridazine The crude product waspurified by chromatography over silica gel, eluting with a step gradientof 10%-25% ethyl acetate in dichloromethane.

¹H NMR; IS-MS, m/e 494.2 (m+1), 492.2 (m−1); Analysis for C₂₂H₂₅Cl₂N₅O₄:Calcd: C, 53.45; H, 5.10; N, 14.17; Found: C, 53.33; H, 4.95; N, 13.90.

E.5-Chloro-N-(6-chloropyridazin-3-yl)-2-[(4-piperidinylcarbonyl)amino]benzamideTrifluoroacetate.

Using methods substantially equivalent to those described in Example9-B,5-chloro-N-(6-chloropyridazin-3-yl)-2-[(4-piperidinylcarbonyl)amino]benzamidetrifluoroacetate (0.58 g, 98%) was prepared from2-(1-tert-butoxycarbonylpiperidin-4-ylcarbonyl)amino]-5-chloro-N-(6-chloropyridazin-3-yl)benzamide.

¹H NMR; IS-MS, m/e 394.1 (m+1), 392.1 (m−1); Analysis forC₁₇H₁₇Cl₂N₅O₂.1.0C₂HF₃O₂: Calcd: C, 44.90; H, 3.57; N, 13.78; F, 11.21;Found: C, 45.17; H, 3.80; N, 13.52; F, 11.45.

F.5-Chloro-N-(6-chloropyridazin-3-yl)-2-[(1-isopropylpiperidin-4-ylcarbonyl)amino]benzamideHydrochloride.

Using methods substantially equivalent to those described in Example231-E,5-chloro-N-(6-chloropyridazin-3-yl)-2-[(1-isopropylpiperidin-4-ylcarbonyl)amino]benzamidehydrochloride (0.23 g, 50%) was prepared from5-chloro-N-(6-chloropyridazin-3-yl)-2-[(4-piperidinylcarbonyl)amino]benzamidetrifluoroacetate. The product was purified by RPHPLC, eluting with agradient from 20% through 50% acetonitrile in 0.05% aqueous hydrochloricacid.

¹H NMR; IS-MS, m/e 436.3 (m+1), 434.3 (m−1); Analysis forC₂₀H₂₃Cl₂N₅O₂.2.4HCl.0.9H₂O: Calcd: C, 44.48; H, 5.08; N, 12.97; Cl,28.89; Found: C, 44.21; H, 5.11; N, 12.63; Cl, 28.93.

EXAMPLE 237 Preparation ofN-(5-Chloropyridin-2-yl)-2-[(1-isopropylpiperidin-4-ylcarbonyl)amino]-5-methoxycarbonylbenzamide

A. 2-Amino-N-(5-chloropyridin-2-yl)-5-iodobenzamide.

Using methods substantially equivalent to those described in Example173-C, 2-amino-N-(5-chloropyridin-2-yl)-5-iodobenzamide (0.49 g, 32%)was prepared from 2-amino-N-(5-chloropyridin-2-yl)benzamide The crudeproduct was purified by chromatography over silica gel, eluting with astep gradient of 5-10% ethyl acetate in dichloromethane The purified bychromatography product was slurried in isopropanol and filtered.

¹H NMR; IS-MS, m/e 373.8 (m+1), 371.8 (m−1); Analysis for C₁₂H₉ClIN₃O:Calcd: C, 38.58; H, 2.43; N, 11.25; Found: C, 38.64; H, 2.76; N, 11.22.

B.2-[(1-tert-Butoxycarbonylpiperidin-4-ylcarbonyl)amino]-N-(5-chloropyridin-2-yl)-5-iodobenzamide.

Using methods substantially equivalent to those described in Example25-D,2-[(1-tert-butoxycarbonylpiperidin-4-ylcarbonyl)amino]-N-(5-chloropyridin-2-yl)-5-iodobenzamide(8.6 g, 62%) was prepared from2-amino-N-(5-chloropyridin-2-yl)-5-iodobenzamide.

¹H NMR; IS-MS, m/e 584.8 (m+1), 582.9 (m−1); Analysis for C₂₃H₂₆ClIN₄O₄:Calcd: C, 47.23; H, 4.48; N, 9.58; Found: C, 46.96; H, 4.45; N, 9.68.

C.N-(5-Chloropyridin-2-yl)-5-iodo-2-[(4-piperidinylcarbonyl)amino]benzamideTrifluoroacetate.

Using methods substantially equivalent to those described in Example9-B,N-(5-chloropyridin-2-yl)-5-iodo-2-[(4-piperidinylcarbonyl)amino]benzamidetrifluoroacetate (1.86 g, 90%) was prepared from2-[(1-tert-butoxycarbonylpiperidin-4-ylcarbonyl)amino]-N-(5-chloropyridin-2-yl)-5-iodobenzamide.

¹H NMR; IS-MS, m/e 484.9(m+1), 482.9 (m−1); Analysis forC₁₈H₁₈ClIN₄O₂.1.1C₂HF₃O₂: Calcd: C, 39.76; H, 3.16; N, 9.18; Found: C,39.70; H, 3.20; N, 9.35.

D.N-(5-Chloropyridin-2-yl)-5-iodo-2-[(1-isopropylpiperidin-4-ylcarbonyl)amino]benzamide.

Using methods substantially equivalent to those described in Example231-E,N-(5-chloropyridin-2-yl)-5-iodo-2-[(1-isopropylpiperidin-4-ylcarbonyl)amino]benzamide(0.87 g, 65%) was prepared fromN-(5-chloropyridin-2-yl)-5-iodo-2-[(4-piperidinylcarbonyl)amino]benzamidetrifluoroacetate.

¹H NMR; IS-MS, m/e 526.9 (m+1), 525.0 (m−1); Analysis forC₂₁H₂₄ClIN₄O₂.1.4H₂O: Calcd: C, 45.69; H, 4.89; N, 10.15; Found: C,45.37; H, 4.68; N, 10.02.

E.N-(5-Chloropyridin-2-yl)-2-[(1-isopropylpiperidin-4-ylcarbonyl)amino]-5-methoxycarbonylbenzamide.

To a stirring solution ofN-(5-chloropyridin-2-yl)-5-iodo-2-(1-isopropylpiperidin-4-ylcarbonyl)amino]benzamide(0.49 g, 0.92 mmol) in N,N-dimethylformamide (10 mL) was addedtriethylamine (0.4 mL, 2.8 mmol), followed by PdCl₂(PPh₃)₂, and thenmethanol (5 mL). The mixture was placed under a carbon monoxideatmosphere, heated to 60° C. for 18 h, and concentrated in vacuo. Thecrude product was purified by chromatography over silica gel, elutingwith a step gradient of 10-20% 2 M solution of ammonia/methanol indichloromethane The chromatography product was recrystallized frommethanol to give 0.16 g (38%) of a white solid.

¹H NMR; IS-MS, m/e 459.9 (m−1); Analysis for C₂₃H₂₇ClN₄O₄: Calcd: C,60.19; H, 5.93; N, 12.21; Found: C, 60.03; H, 5.85; N, 12.07.

EXAMPLE 238 Preparation of6-Chloro-N-(5-chloropyridin-2-yl)-2-[(1-isopropylpiperidin-4-ylcarbonyl)amino]benzamide

A.2-[(1-tert-Butoxycarbonylpiperidin-4-ylcarbonyl)amino]-6-chlorobenzoicAcid.

Using methods substantially equivalent to those described in Example25-D, crude2-[(1-tert-butoxycarbonylpiperidin-4-ylcarbonyl)amino]-6-chloro benzoicacid (0.56 g, 45%) was prepared from 2-amino-6-chlorobenzoic acid.

¹H NMR; IS-MS, m/e 382.9 (m+1), 380.9 (m−1);

B.2-[(1-tert-Butoxycarbonylpiperidin-4-yl)-5-chloro-4H-3,1-benzoxazin-4-one.

Using methods substantially equivalent to those described in Example51-C,2-[(1-tert-butoxycarbonylpiperidin-4-yl)-5-chloro-4H-3,1-benzoxazin-4-one(0.42 g, 76%) was prepared from crude2-[(1-tert-butoxycarbonylpiperidin-4-ylcarbonyl)amino]-6-chlorobenzoicacid. ¹H NMR; FD-MS, m/e 364.1 (m+1); Analysis for C₁₈H₂₁ClN₂O₄: Calcd:C, 59.26; H, 5.80; N, 7.68; Found: C, 59.30; H, 5.71; N, 7.65.

C.2-[(1-tert-Butoxycarbonylpiperidin-4-ylcarbonyl)amino]-6-chloro-N-(5-chloropyridin-2-yl)benzamide.

Using methods substantially equivalent to those described in Example51-D,2-[(1-tert-butoxycarbonylpiperidin-4-ylcarbonyl)amino]-6-chloro-N-(5-chloropyridin-2-yl)benzamide(0.34 g, 69%) was prepared from2-[(1-tert-butoxycarbonylpiperidin-4-yl)-5-chloro-4H-3,1-benzoxazin-4-one.

¹H NMR; IS-MS, m/e 493.2 (m+1), 491.2 (m−1); Analysis forC₂₃H₂₆Cl₂N₄O₄.0.2H₂O: Calcd: C, 55.58; H, 5.35; N, 11.27; Found: C,55.35; H, 5.40; N, 11.35.

D.6-Chloro-N-(5-chloropyridin-2-yl)-2-[(4-piperidinylcarbonyl)amino]benzamideTrifluoroacetate.

Using methods substantially equivalent to those described in Example9-B,6-chloro-N-(5-chloropyridin-2-yl)-2-[(4-piperidinylcarbonyl)amino]benzamidetrifluoroacetate (0.28 g, 91%) was prepared from2-[(1-tert-butoxycarbonylpiperidin-4-ylcarbonyl)amino]-6-chloro-N-(5-chloropyridin-2-yl)benzamide.

¹H NMR; IS-MS, m/e 393.1 (m+1), 391.2 (m−1); Analysis forC₁₈H₁₈Cl₂N₄O₂.1.0C₂HF₃O₂: Calcd: C, 47.35; H, 3.78; N, 11.04; F, 11.24;Found: C, 47.38; H, 3.92; N, 10.92; F, 11.47.

E.6-Chloro-N-(5-chloropyridin-2-yl)-2-[(1-isopropylpiperidin-4-ylcarbonyl)amino]benzamide.

Using methods substantially equivalent to those described in Example231-E,6-chloro-N-(5-chloropyridin-2-yl)-2-[(1-isopropylpiperidin-4-ylcarbonyl)amino]benzamide(0.86 g, 51%) was prepared from6-chloro-N-(5-chloropyridin-2-yl)-2-[(4-piperidinylcarbonyl)amino]benzamidetrifluoroacetate.

¹H NMR; IS-MS, m/e 435.2 (m+1), 433.4 (m−1); Analysis forC₂₁H₂₄Cl₂N₄O₂.0.1H₂O: Calcd: C, 57.70; H, 5.58; N, 12.82; Found: C,57.33; H, 5.50; N, 12.73.

EXAMPLE 239 Preparation ofN-(5-Chloropyridin-2-yl)-6-fluoro-2-[(1-isopropylpiperidin-4-ylcarbonyl)amino]benzamide

A. 2-Fluoro-6-nitrobenzoic Acid.

To a stirring suspension of potassium permanganate (102 g, 0.65 mol) inwater (1.4 L) was added 2-fluoro-6-nitrotoluene The reaction was heatedat reflux for 4 h, cooled to room temperature, filtered, and washed withdiethyl ether. The aqueous phase was acidified to pH 2 with concentratedhydrochloric acid and extracted with ethyl acetate. The organic phasewas washed with brine, dried over magnesium sulfate, filtered, andconcentrated in vacuo to give 11.81 g (40%).

¹H NMR; IS-MS, m/e 184.0 (m−1); Analysis for C₇H₄FNO₄: Calcd: C, 45.42;H, 2.18; N, 7.57; Found: C, 45.22; H, 2.29; N, 7.27.

B. N-(5-Chloropyridin-2-yl)-6-fluoro-2-nitrobenzamide.

Using methods substantially equivalent to those described in Example231-A, N-(5-chloropyridin-2-yl)-6-fluoro-2-nitrobenzamide (7.83 g, 58%)was prepared from 2-amino-5-chloropyridine and 2-fluoro-6-nitrobenzoicacid. The crude product was purified by chromatography over silica gel,eluting with dichloromethane.

¹H NMR; IS-MS, m/e 296.2 (m+1), 294.1 (m−1); Analysis for C₁₂H₇ClFN₃O₃:Calcd: C, 48.75; H, 2.39; N, 14.21; Found: C, 48.89; H, 2.42; N, 14.14.

C. 2-Amino-N-(5-chloropyridin-2-yl)-6-fluorobenzamide.

Using methods substantially equivalent to those described in Example2-B, 2-amino-N-(5-chloropyridin-2-yl)-6-fluorobenzamide (6.75 g, 97%)was prepared from N-(5-chloropyridin-2-yl)-6-fluoro-2-nitrobenzamide.

¹H NMR; IS-MS, m/e 264.1 (m−1); Analysis for C₁₂H₉ClFN₃O: Calcd: C,54.25; H, 3.41; N, 15.82; Found: C, 54.30; H, 3.37; N, 15.63.

D.2-[(-tert-Butoxycarbonylpiperidin-4-ylcarbonyl)amino]-N-(5-chloropyridin-2-yl)-6-fluorobenzamide.

Using methods substantially equivalent to those described in Example25-D,2-[(1-tert-butoxycarbonylpiperidin-4-ylcarbonyl)amino]-N-(5-chloropyridin-2-yl)-6-fluorobenzamide(1.23 g, 69%) was prepared from2-amino-N-(5-chloropyridin-2-yl)-6-fluorobenzamide. The crude productwas purified by chromatography over silica gel, eluting with a stepgradient of 10-15% ethyl acetate in dichloromethane.

¹H NMR; IS-MS, m/e 477.2 (m+1), 475.1 (m−1); Analysis for C₂₃H₂₆ClFN₄O₄:Calcd: C, 57.92; H, 5.49; N, 11.75; Found: C, 62.90; H, 6.12; N, 12.38.

E.N-(5-Chloropyridin-2-yl)-6-fluoro-2-[(4-piperidinylcarbonyl)amino]benzamideTrifluoroacetate.

Using methods substantially equivalent to those described in Example9-B,N-(5-chloropyridin-2-yl)-6-fluoro-2-[(4-piperidinylcarbonyl)amino]benzamidetrifluoroacetate (0.95 g, 92%) was prepared from2-[(1-tert-butoxycarbonylpiperidin-4-ylcarbonyl)amino]-N-(5-chloropyridin-2-yl)-6-fluorobenzamide.

¹H NMR; IS-MS, m/e 377.3 (m+1), 375.2 (m−1); Analysis forC₁₈H₁₈ClFN₄O₂.1.0C₂HF₃O₂: Calcd: C, 48.94; H, 3.90; N, 11.41; F, 15.48;Found: C, 49.20; H, 3.87; N, 11.11; F, 16.04.

F.N-(5-Chloropyridin-2-yl)-6-fluoro-2-[(1-isopropylpiperidin-4-ylcarbonyl)amino]benzamide.

Using methods substantially equivalent to those described in Example231-E,N-(5-chloropyridin-2-yl)-6-fluoro-2-[(1-isopropylpiperidin-4-ylcarbonyl)amino]benzamidehydrochloride (0.345 g, 80%) was prepared fromN-(5-chloropyridin-2-yl)-6-fluoro-2-[(4-piperidinylcarbonyl)amino]-benzamidetrifluoroacetate.

¹H NMR; IS-MS, m/e 419.2 (m+1), 417.3 (m−1); Analysis forC₂₁H₂₄ClFN₄O₂.0.6H₂O: Calcd: C, 58.70; H, 5.91; N, 13.04; Found: C,58.46; H, 5.52; N, 13.21.

EXAMPLE 240 Preparation ofN-(5-Chloropyridin-2-yl)-5-ethyl-2-[(1-isopropylpiperidin-4-ylcarbonyl)amino]benzamide

A. 4-Ethyl-2-iodoaniline.

Using methods substantially equivalent to those described in Example173-C, 4-ethyl-2-iodoaniline (22.44 g, 35%) was prepared from4-ethylaniline.

¹H NMR; IS-MS, m/e 248.2 (m+1); Analysis for C₈H₁₀NI: Calcd: C, 38.89;H, 4.08; N, 5.67; Found: C, 38.44; H, 3.90; N, 5.49.

B.2-[(1-tert-Butoxycarbonylpiperidin-4-ylcarbonyl)amino]-5-ethyl-1-iodobenzene.

Using methods substantially equivalent to those described in Example25-D,2-[(1-tert-butoxycarbonylpiperidin-4-ylcarbonyl)amino]-5-ethyl-1-iodobenzene(4.56 g, 25%) was prepared from 4-ethyl-2-iodoaniline.

¹H NMR; IS-MS, m/e 459.4 (m+1), 457.3 (m−1); Analysis for C₁₉H₂₇IN₂O₃:Calcd: C, 49.79; H, 5.94; N, 6.11; Found: C, 50.32; H, 6.09; N, 6.07.

C.2-[(1-tert-Butoxycarbonylpiperidin-4-yl)-6-ethyl-4H-3,1-benzoxazin-4-one.

Using methods substantially equivalent to those described in Example173-E,2-[(1-tert-butoxycarbonylpiperidin-4-yl)-6-ethyl-4H-3,1-benzoxazin-4-one(2.34 g, 73%) was prepared from2-[(1-tert-butoxycarbonylpiperidin-4-ylcarbonyl)amino]-5-ethyl-1-iodobenzene.

¹H NMR; FD-MS, m/e 390 (m+1); Analysis for C₂₀H₂₆N₂O₄: Calcd: C, 67.02;H, 7.31; N, 7.82; Found: C, 66.42; H, 7.30; N, 7.64.

D.2-[(1-tert-Butoxycarbonylpiperidin-4-ylcarbonyl)amino]-N-(5-chloropyridin-2-yl)-5-ethylbenzamide.

Using methods substantially equivalent to those described in Example51-D,2-[(1-tert-butoxycarbonylpiperidin-4-ylcarbonyl)amino]-N-(5-chloropyridin-2-yl)-5-ethylbenzamide(1.27 g, 47%) was prepared from2-[(1-tert-butoxycarbonylpiperidin-4-yl)-6-ethyl-4H-3,1-benzoxazin-4-one.

¹H NMR; IS-MS, m/e 487.4 (m+1), 485.5 (m−1); Analysis for C₂₅H₃₁ClN₄O₄:Calcd: C, 61.66; H, 6.42; N, 11.50; Found: C, 61.85; H, 6.08; N, 11.31.

E.N-(5-Chloropyridin-2-yl)-5-ethyl-2-[(4-piperidinylcarbonyl)amino]benzamideTrifluoroacetate.

Using methods substantially equivalent to those described in Example9-B,N-(5-chloropyridin-2-yl)-5-ethyl-2-[(4-piperidinylcarbonyl)amino]benzamidetrifluoroacetate (1.01 g, 89%) was prepared from2-[(1-tert-butoxycarbonylpiperidin-4-ylcarbonyl)amino]-N-(5-chloropyridin-2-yl)-5-ethylbenzamide.

¹H NMR; IS-MS, m/e 387.1 (m+1), 385.2 (m−1); Analysis forC₂₀H₂₃ClN₄O₂.1.0C₂HF₃O₂: Calcd: C, 52.75; H, 4.83; N, 11.19; F, 11.38;Found: C, 52.95; H, 4.86; N, 10.83; F, 11.89.

F.N-(5-Chloropyridin-2-yl)-5-ethyl-2-[(1-isopropylpiperidin-4-ylcarbonyl)amino]benzamide.

Using methods substantially equivalent to those described in Example231-E,N-(5-chloropyridin-2-yl)-5-ethyl-2-[(1-isopropylpiperidin-4-ylcarbonyl)amino]benzamide(0.38 g, 89%) was prepared fromN-(5-chloropyridin-2-yl)-5-ethyl-2-[(4-piperidinylcarbonyl)amino]benzamidetrifluoroacetate.

¹H NMR; IS-MS, m/e 429.2 (m+1), 427.2 (m−1); Analysis for C₂₃H₂₉ClN₄O₂:Calcd: C, 64.40; H, 6.81; N, 13.06; Found: C, 64.10; H, 6.70; N, 12.85.

EXAMPLE 241 Preparation ofN-(5-Chloropyridin-2-yl)-5-isopropyl-2-[(1-isopropylpiperidin-4-ylcarbonyl)amino]benzamide

A. 2-Iodo-4-isopropylaniline.

Using methods substantially equivalent to those described in Example173-C, 2-iodo-4-isopropylaniline (33.62 g, 50%) was prepared from4-isopropylaniline.

¹H NMR; Analysis for C₉H₁₂NI: Calcd: C, 41.40; H, 4.63; N, 5.36; Found:C, 56.40; H, 4.73; N, 10.76.

B.2-[(1-tert-Butoxycarbonylpiperidin-4-ylcarbonyl)amino]-1-iodo-5-isopropylbenzene.

Using methods substantially equivalent to those described in Example25-D,2-[(1-tert-butoxycarbonylpiperidin-4-ylcarbonyl)amino]-1-iodo-5-isopropylbenzene(2.05 g, 43%) was prepared from 2-iodo-4-isopropylaniline.

¹H NMR; IS-MS, m/e 473.1 (m+1), 471.2 (m−1); Analysis for C₂₀H₂₉IN₂O₃:Calcd: C, 50.85; H, 6.19; N, 5.93; Found: C, 44.16; H, 5.32; N, 5.67.

C.2-[(1-tert-Butoxycarbonylpiperidin-4-yl)-6-isopropyl-4H-3,1-benzoxazin-4-one.

Using methods substantially equivalent to those described in Example173-E,2-[(1-tert-butoxycarbonylpiperidin-4-yl)-6-isopropyl-4H-3,1-benzoxazin-4-one(1.11 g, 94%) was prepared from2-[(1-tert-butoxycarbonylpiperidin-4-ylcarbonyl)amino]-1-iodo-5-isopropylbenzene.

¹H NMR; IS-MS, m/e 373.2 (m+1); Analysis for C₂₁H₂₈N₂O₄: Calcd: C,67.72; H, 7.58; N, 7.52; Found: C, 68.11; H, 7.74; N, 7.62.

D.2-[(1-tert-Butoxycarbonylpiperidin-4-ylcarbonyl)amino]-N-(5-chloropyridin-2-yl)-5-isopropylbenzamide.

Using methods substantially equivalent to those described in Example51-D,2-[(1-tert-butoxycarbonylpiperidin-4-ylcarbonyl)amino]-N-(5-chloropyridin-2-yl)-5-isopropylbenzamide(0.55 g, 41%) was prepared from2-[(1-tert-butoxycarbonylpiperidin-4-yl)-6-isopropyl-4H-3,1-benzoxazin-4-one.

¹H NMR; IS-MS, m/e 501.1 (m+1), 499.2 (m−1); Analysis for C₂₆H₃₃ClN₄O₄:Calcd: C, 62.33; H, 6.64; N, 11.18; Found: C, 60.69; H, 6.34; N, 11.15.

E.N-(5-Chloropyridin-2-yl)-5-isopropyl-2-[(4-piperidinylcarbonyl)amino]benzamideTrifluoroacetate.

Using methods substantially equivalent to those described in Example9-B,N-(5-chloropyridin-2-yl)-5-isopropyl-2-[(4-piperidinylcarbonyl)amino]benzamidetrifluoroacetate (0.45 g, 98%) was prepared from2-[(1-tert-butoxycarbonylpiperidin-4-ylcarbonyl)amino]-N-(5-chloropyridin-2-yl)-5-isopropylbenzamide.

¹H NMR; IS-MS, m/e 401.2 (m+1), 399.2 (m−1); Analysis forC₂₁H₂₅ClN₄O₂.1.0C₂HF₃O₂.0.1H₂O: Calcd: C, 53.46; H, 5.11; N, 10.84; F,11.03; Found: C, 53.22; H, 5.04; N, 10.98; F, 11.50.

F.N-(5-Chloropyridin-2-yl)-5-isopropyl-2-[(1-isopropylpiperidin-4-ylcarbonyl)amino]benzamide.

Using methods substantially equivalent to those described in Example231-E,N-(5-chloropyridin-2-yl)-5-isopropyl-2-[(1-isopropylpiperidin-4-ylcarbonyl)amino]-benzamide(0.38 g, 89%) was prepared fromN-(5-chloropyridin-2-yl)-5-isopropyl-2-[(4-piperidinylcarbonyl)amino]-benzamidetrifluoroacetate.

¹H NMR; IS-MS, m/e 443.2 (m+1), 441.3 (m−1); Analysis forC₂₄H₃₁ClN₄O₂.0.3H₂O: Calcd: C, 64.29; H, 7.10; N, 12.50; Found: C,64.10; H, 6.97; N, 12.23.

EXAMPLE 242 Preparation of4-Chloro-N-(5-chloropyridin-2-yl)-2-[(1-isopropylpiperidin-4-ylcarbonyl)amino]benzamide

A.2-[(1-tert-Butoxycarbonylpiperidin-4-ylcarbonyl)amino]-4-chloro-N-(5-chloropyridin-2-yl)benzamide.

Using methods substantially equivalent to those described in Example25-D,2-[(1-tert-butoxycarbonylpiperidin-4-ylcarbonyl)amino]-4-chloro-N-(5-chloropyridin-2-yl)benzamide(3.83 g, 97%) was prepared from2-amino-4-chloro-N-(5-chloropyridin-2-yl)benzamide.

¹H NMR; IS-MS, m/e 493.0 (m+1), 491.0 (m−1);

B.4-Chloro-N-(5-chloropyridin-2-yl)-2-[(4-piperidinylcarbonyl)amino]benzamideTrifluoroacetate.

Using methods substantially equivalent to those described in Example9-B,4-chloro-N-(5-chloropyridin-2-yl)-2-[(4-piperidinylcarbonyl)amino]benzamidetrifluoroacetate (3.66 g, 93%) was prepared from2-[(1-tert-butoxycarbonylpiperidin-4-ylcarbonyl)amino]-4-chloro-N-(5-chloropyridin-2-yl)benzamide.

¹H NMR.

C.4-Chloro-N-(5-chloropyridin-2-yl)-2-[(1-isopropylpiperidin-4-ylcarbonyl)amino]benzamide.

Using methods substantially equivalent to those described in Example231-E,4-chloro-N-(5-chloropyridin-2-yl)-2-[(1-isopropylpiperidin-4-ylcarbonyl)amino]benzamide(0.22 g, 51%) was prepared from4-chloro-N-(5-chloropyridin-2-yl)-2-[(4-piperidinylcarbonyl)amino]benzamidetrifluoroacetate.

¹H NMR; IS-MS, m/e 435.2 (m+1), 433.4 (m−1); Analysis forC₂₁H₂₄Cl₂N₄O₂.0.3H₂O: Calcd: C, 57.22; H, 5.63; N, 12.71; Found: C,56.93; H, 5.48; N, 12.64.

EXAMPLE 243 Preparation ofN-(5-Chloropyridin-2-yl)-4-fluoro-2-[(1-isopropylpiperidin-4-ylcarbonyl)amino]benzamide

A.2-[(1-tert-Butoxycarbonylpiperidin-4-ylcarbonyl)amino]-N-(5-chloropyridin-2-yl)-4-fluorobenzamide.

Using methods substantially equivalent to those described in Example25-D,2-[(1-tert-butoxycarbonylpiperidin-4-ylcarbonyl)amino]-N-(5-chloropyridin-2-yl)-4-fluorobenzamide(2.08 g, 55%) was prepared from2-amino-N-(5-chloropyridin-2-yl)-4-fluorobenzamide.

¹H NMR; IS-MS, m/e 477.0 (m+1), 475.0 (m−1).

B.N-(5-Chloropyridin-2-yl)-4-fluoro-2-((4-piperidinylcarbonyl)amino]benzamideTrifluoroacetate.

Using methods substantially equivalent to those described in Example9-B,N-(5-chloropyridin-2-yl)-4-fluoro-2-[(4-piperidinylcarbonyl)amino]benzamidetrifluoroacetate (1.68 g, 100%) was prepared from2-[(1-tert-butoxycarbonylpiperidin-4-ylcarbonyl)amino]-N-(5-chloropyridin-2-yl)-4-fluorobenzamide.

¹H NMR; IS-MS, m/e 377.0 (m+1), 375.0 (m−1).

C.N-(5-Chloropyridin-2-yl)-4-fluoro-2-[(1-isopropylpiperidin-4-ylcarbonyl)amino]benzamide.

Using methods substantially equivalent to those described in Example231-E,N-(5-chloropyridin-2-yl)-4-fluoro-2-[(1-isopropylpiperidin-4-ylcarbonyl)amino]benzamide(0.32 g, 74%) was prepared fromN-(5-chloropyridin-2-yl)-4-fluoro-2-[(4-piperidinylcarbonyl)amino]benzamidetrifluoroacetate.

¹H NMR; IS-MS, m/e 419.2 (m+1), 417.2 (m−1); Analysis forC₂₁H₂₄ClFN₄O₂.0.3H₂O: Calcd: C, 59.44; H, 5.84; N, 13.21; Found: C,59.22; H, 5.60; N, 13.14.

EXAMPLE 244 Preparation ofN-(5-Chloropyridin-2-yl)-5-iodo-2-[(1-isopropylpiperidin-4-ylcarbonyl)amino]benzamide

A. N-(5-Chloropyridin-2-yl)-2-nitrobenzamide.

To a stirring solution of 2-amino-5-chloropyridine (3.7 g, 29 mmol) andpyridine (7.3 mL, 90 mmol) in dichloromethane was added 2-nitrobenzoylchloride (5.7 g, 30 mmol). After stirring for 4 h, the solvents wereremoved in vacuo and the residue partitioned between ethyl acetate andwater. The organic phase was washed with brine, dried over magnesiumsulfate, filtered, and concentrated in vacuo. After standing at roomtemperature overnight, the mixture was filtered to give 6.4 g (79%) of awhite solid.

¹H NMR; FD-MS, m/e 276.9 (m); Analysis for C₁₂H₈ClN₃O₃: Calcd: C, 51.91;H, 2.90; N, 15.13; Found: C, 52.61; H, 2.89; N, 15.29.

B. N-(5-Chloropyridin-2-yl)-2-aminobenzamide.

To a solution of N-(5-chloropyridin-2-yl)-2-nitrobenzamide (2 g, 7.2mmol) in tetrahydrofuran (50 mL) and ethyl acetate (50 mL) was addedRaney nickel (0.2 g) and the mixture was placed under hydrogen (4.1 bar)in a high pressure apparatus. After shaking overnight, the mixture wasfiltered and concentrated in vacuo and purified by flash chromatographyto give 1.5 g (83%) of an off-white solid.

¹H NMR.

C. 2-Amino-N-(5-chloropyridin-2-yl)-5-iodobenzamide.

To an ice cold stirring suspension ofN-(5-chloropyridin-2-yl)-2-aminobenzamide (1.01 g, 4.09 mmol) in ethanol(80 mL) was added a mixture of iodine (1.04 g, 4.10 mmol) and silversulfate (1.29 g, 4.09 mmol). The mixture was stirred at room temperaturefor 3 d and filtered. The filtrate was concentrated, partitioned betweendichloromethane and saturated aqueous sodium bicarbonate. The organicphase was dried over magnesium sulfate, filtered, and concentrated invacuo. The crude product was purified by chromatography over silica gel,eluting with a step gradient of 5-10% ethyl acetate in dichloromethaneThe chromatography product was slurried in isopropanol and filtered togive 0.49 g (32%) of an orange solid.

¹H NMR; IS-MS, m/e 373.8 (m+1), 371.8 (m−1); Analysis for C₁₂H₉ClIN₃O:Calcd: C, 38.58; H, 2.43; N, 11.25; Found: C, 38.64; H, 2.76; N, 11.22.

D.2-[(1-tert-Butoxycarbonylpiperidin-4-ylcarbonyl)amino]-N-(5-chloropyridin-2-yl)-5-iodobenzamide.

To a stirring solution of 1-Boc-isonipecotic acid (15.26 g, 66.55 mmol)in methanol (135 mL) was added sodium methoxide (3.8 g, 66.8 mmol).After stirring for 1 h, the solvent was removed in vacuo. A portion ofthe residue (8.92 g, 35.5 mmol) was suspended in dichloromethane (95 mL)and oxalyl chloride (4 mL, 45 mmol) was added, followed by a couple ofdrops of N,N-dimethylformamide. After stirring for 1 h, the solvent wasremoved in vacuo. The residue was suspended in dichloromethane (45 mL)and added to a solution of2-amino-N-(5-chloropyridin-2-yl)-5-iodobenzamide (8.86 g, 23.7 mmol),N,N-diisopropylethylamine (5 mL, 28 mmol), and4-(N,N-dimethylamino)pyridine (0.33 g, 2.7 mmol) in dichloromethane (50mL). After stirring 19 h, the reaction mixture was partitioned betweendichloromethane and saturated aqueous sodium bicarbonate. The organicphase was dried over magnesium sulfate, filtered, and concentrated invacuo. The residue was slurried in diethyl ether and filtered to give8.6 g (62%) of a pink solid.

¹H NMR; IS-MS, m/e 584.8 (m+1), 582.9 (m−1); Analysis for C₂₃H₂₆ClIN₄O₄:Calcd: C, 47.23; H, 4.48; N, 9.58; Found: C, 46.96; H, 4.45; N, 9.68.

E.N-(5-Chloropyridin-2-yl)-5-iodo-2-[(4-piperidinylcarbonyl)amino]benzamideTrifluoroacetate.

To a stirring solution of2-[(1-tert-butoxycarbonylpiperidin-4-ylcarbonyl)amino]-N-(5-chloropyridin-2-yl)-5-iodobenzamide(2.0 g, 3.45 mmol) in dichloromethane (65 mL) and anisole (2 mL, 18mmol) was added trifluoroacetic acid (6.7 mL, 87 mmol). The reactionsolution was stirred at room temperature for 4 h, concentrated in vacuo,treated with diethyl ether and concentrated (3×), treated with diethylether, sonicated, and filtered to give 1.86 g (90%) of a gray solid.

¹H NMR; IS-MS, m/e 484.9(m+1), 482.9 (m−1); Analysis forC₁₈H₁₈ClIN₄O₂.1.1C₂HF₃O₂: Calcd: C, 39.76; H, 3.16; N, 9.18; Found: C,39.70; H, 3.20; N, 9.35.

F.N-(5-Chloropyridin-2-yl)-5-iodo-2-[(1-isopropylpiperidin-4-ylcarbonyl)amino]benzamide.

To a stirring suspension ofN-(5-chloropyridin-2-yl)-5-iodo-2-[(4-piperidinylcarbonyl)amino]benzamidetrifluoroacetate (1.5 g, 2.52 mmol) in methanol (25 mL) was addedacetone (25 mL), followed by acetic acid (0.6 mL, 10 mmol), and thensodium cyanoborohydride (0.67 g, 10 mmol). After stirring overnight, thesolution was treated with saturated aqueous ammonium acetate solution,concentrated, and partitioned between dichloromethane and saturatedaqueous sodium bicarbonate. The organic phase was washed with brine,dried over magnesium sulfate, filtered, and concentrated. The crudeproduct was purified by chromatography over silica gel, eluting with astep gradient of 5-15% 2 M solution of ammonia/methanol indichloromethane. The chromatography product was slurried in diethylether and filtered to give 0.87 g (65%) of a white solid.

¹H NMR; IS-MS, m/e 526.9 (m+1), 525.0 (m−1); Analysis forC₂₁H₂₄ClIN₄O₂.1.4H₂O: Calcd: C, 45.69; H, 4.89; N, 10.15; Found: C,45.37; H, 4.68; N, 10.02.

EXAMPLE 245 Preparation ofN-(5-Chloropyridin-2-yl)-2-[(1-isopropylpiperidin-4-ylcarbonyl)amino]-5-phenylbenzamideHydrochloride

To a stirring solution ofN-(5-chloropyridin-2-yl)-5-iodo-2-[(1-isopropylpiperidin-4-ylcarbonyl)amino]benzamide(0.29 g, 0.54 mmol), tetrakis(triphenylphosphine)palladium(0) (35 mg,0.03 mmol), and phenylboronic acid (81 mg, 0.66 mmol) in toluene (5 mL)was added water (0.55 mL) and a 2 M aqueous sodium carbonate solution(0.55 mL, 1.1 mmol). The mixture was heated to 85-95° C. for 1 h, cooledto room temperature, partitioned between ethyl acetate and saturatedaqueous sodium bicarbonate. The organic phase was treated with 0.002 Naqueous hydrochloric acid. To the aqueous phase was addeddichloromethane followed by saturated aqueous sodium bicarbonate untilpH 8-9. The phases were separated and the organic phase wasconcentrated. The crude product was purified by RPHPLC, eluting with agradient from 25% through 65% acetonitrile in 0.05% aqueous hydrochloricacid, to give 0.16 g (57%) of a yellow solid.

¹H NMR; IS-MS, m/e 477.0 (m+1), 475.0 (m−1); Analysis forC₂₇H₂₉ClN₄O₂.1.8HCl.0.9H₂O: Calcd: C, 58.03; H, 5.88; N, 10.03; Cl,17.76; Found: C, 58.08; H, 5.65; N, 9.79; Cl, 17.58.

EXAMPLE 246 Preparation ofN-(5-Chloropyridin-2-yl)-2-[(1-isopropylpiperidin-4-ylcarbonyl)amino]-5-(3-thienyl)benzamideHydrochloride

Using methods substantially equivalent to those described in Example245,N-(5-chloropyridin-2-yl)-2-[(1-isopropylpiperidin-4-ylcarbonyl)amino]-5-(3-thienyl)benzamidehydrochloride (0.25 g, 50%) was prepared fromN-(5-chloropyridin-2-yl)-5-iodo-2-[(1-isopropylpiperidin-4-ylcarbonyl)amino]benzamide.

¹H NMR; IS-MS, m/e 482.9 (m+1), 481.0 (m−1); Analysis forC₂₅H₂₇ClN₄O₂S.1.7HCl.0.7H₂O: Calcd: C, 53.85; H, 5.44; N, 10.05; Cl,17.17; Found: C, 53.82; H, 5.53; N, 9.86; Cl, 17.01.

EXAMPLE 247 Preparation ofN-(5-Chloropyridin-2-yl)-2-[(1-isopropylpiperidin-4-ylcarbonyl)amino]-3-methoxybenzamideHydrochloride

A. N-(5-Chloropyridin-2-yl)-3-methoxy-2-nitrobenzamide.

To a stirring suspension of 3-methoxy-2-nitrobenzoic acid (14.5 g, 73.5mmol) in dichloromethane (100 mL) was added a couple of drops ofN,N-dimethylformamide followed by oxalyl chloride (6.7 mL, 77.1 mmol).The reaction was stirred at room temperature overnight and the residuetransferred slowly to an ice cold solution of 2-amino-5-chloropyridine(9 g, 70 mmol) and pyridine (20 mL) in dichloromethane (200 mL). Thereaction was stirred overnight, treated with water, and concentrated.The resulting mixture was treated with ethyl acetate, washedconsecutively with aqueous citric acid, saturated aqueous sodiumbicarbonate, dried over magnesium sulfate, filtered, and concentrated invacuo. The crude product was purified by recrystallization from tolueneto give 17 g (79%) of a white solid.

¹H NMR; ESI+MS, m/e 308.0 (m+1); Analysis for C₁₃H₁₀ClN₃O₄: Calcd: C,50.75; H, 3.28; N, 13.66; Found: C, 51.60; H, 2.75; N, 13.44.

B. 2-Amino-N-(5-chloropyridin-2-yl)-3-methoxybenzamide.

Using methods substantially equivalent to those described in Example244-B, 2-amino-N-(5-chloropyridin-2-yl)-3-methoxybenzamide (11.5 g, 75%)was prepared from N-(5-chloropyridin-2-yl)-3-methoxy-2-nitrobenzamide.

¹H NMR; ES-MS, m/e 278.1 (m+1); Analysis for C₁₃H₁₂ClN₃O₂: Calcd: C,56.23; H, 4.36; N, 15.13; Found: C, 55.95; H, 4.48; N, 14.86.

C.2-[(1-tert-Butoxycarbonylpiperidin-4-ylcarbonyl)amino]-N-(5-chloropyridin-2-yl)-3-methoxybenzamide.

Using methods substantially equivalent to those described in Example244-D,2-[(1-tert-butoxycarbonylpiperidin-4-ylcarbonyl)amino]-N-(5-chloropyridin-2-yl)-3-methoxybenzamide(1.50 g, 85%) was prepared from2-amino-N-(5-chloropyridin-2-yl)-3-methoxybenzamide.

¹H NMR; IS-MS, m/e 489.3 (m+1), 487.5 (m−1); Analysis for C₂₄H₂₉ClN₄O₅:Calcd: C, 58.95; H, 5.98; N, 11.46; Found: C, 58.73; H, 5.92; N, 11.23.

D.N-(5-Chloropyridin-2-yl)-3-methoxy-2-[(4-piperidinylcarbonyl)amino]benzamideTrifluoroacetate.

Using methods substantially equivalent to those described in Example244-E,N-(5-chloropyridin-2-yl)-3-methoxy-2-[(4-piperidinylcarbonyl)amino]benzamidetrifluoroacetate (1.22 g, 99%) was prepared from2-[(1-tert-butoxycarbonylpiperidin-4-ylcarbonyl)amino]-N-(5-chloropyridin-2-yl)-3-methoxybenzamide.

¹H NMR; IS-MS, m/e 389.2 (m+1), 387.2 (m−1); Analysis forC₁₉H₂₁ClN₄O₃.1.0C₂HF₃O₂: Calcd: C, 50.16; H, 4.41; N, 11.14; F, 11.33;Found: C, 50.09; H, 4.16; N, 10.87; F, 11.46.

E.N-(5-Chloropyridin-2-yl)-2-[(1-isopropylpiperidin-4-ylcarbonyl)amino]-3-methoxybenzamideHydrochloride.

Using methods substantially equivalent to those described in Example244-F,N-(5-chloropyridin-2-yl)-2-[(1-isopropylpiperidin-4-ylcarbonyl)amino]-3-methoxybenzamidehydrochloride (0.34 g, 37%) was prepared fromN-(5-chloropyridin-2-yl)-3-methoxy-2-[(4-piperidinylcarbonyl)amino]benzamidetrifluoroacetate. To a stirring solution of the purified product indichloromethane was added 1.0 N hydrochloric acid in diethyl ether untilprecipitate formed. The mixture was filtered to give the title compound.

¹H NMR; IS-MS, m/e 431.3 (m+1), 429.3 (m−1); Analysis forC₂₂H₂₇ClN₄O₃.1.1HCl.0.4H₂O: Calcd: C, 55.25; H, 6.09; N, 11.72; Cl,15.57; Found: C, 55.03; H, 5.90; N, 11.54; Cl, 15.30.

EXAMPLE 248 Preparation of5-Acetyl-N-(5-chloropyridin-2-yl)-2-[(1-isopropylpiperidin-4-ylcarbonyl)amino]benzamideHydrochloride

A. 4-Amino-3-iodoacetophenone.

Using methods substantially equivalent to those described in Example244-C, 4-amino-3-iodoacetophenone (3.9 g, 40%) was prepared from4-aminoacetophenone.

¹H NMR; IS-MS, m/e 261.8 (m+1), 259.9 (m−1); Analysis forC₈H₈INO.0.2C₄H₈O₂: Calcd: C, 37.93; H, 3.47; N, 5.03; Found: C, 37.82;H, 3.22; N, 5.26.

B.5-Acetyl-2-[(1-tert-butoxycarbonylpiperidin-4-ylcarbonyl)amino]-1-iodobenzene.

Using methods substantially equivalent to those described in Example244-D,5-acetyl-2-[(1-tert-butoxycarbonylpiperidin-4-ylcarbonyl)amino]-1-iodobenzene(7.80 g, 48%) was prepared from 4-amino-3-iodoacetophenone.

¹H NMR; IS-MS, m/e 473.0 (m+1), 471.2 (m−1); Analysis for C₁₉H₂₅IN₂O₄:Calcd: C, 48.32; H, 5.34; N, 5.93; Found: C, 48.45; H, 5.49; N, 5.83.

C.5-Acetyl-2-[(1-tert-butoxycarbonylpiperidin-4-ylcarbonyl)amino]benzoicAcid.

To a stirring solution of5-acetyl-2-[(1-tert-butoxycarbonylpiperidin-4-ylcarbonyl)amino]-1-iodobenzene(4.5 g, 9.53 mmol) in acetonitrile (150 mL) was added potassiumcarbonate (6.6 g, 47.7 mmol), followed bytetrakis(triphenylphosphine)palladium(0) (0.55 g, 0.48 mmol), and copperiodide (91 mg, 0.48 mmol). The mixture was placed under an atmosphere ofcarbon monoxide and heated to 80° C. After 3 h, 1 N aqueous sodiumhydroxide (50 mL) was added to the hot reaction solution. The solutionwas stirred for 10 min and concentrated in vacuo. The residue waspartitioned between ethyl acetate and water. The aqueous phase wasfiltered, acidified to pH 3 with citric acid, and extracted with ethylacetate. The organic phase was washed with brine, dried over magnesiumsulfate, filtered, and concentrated in vacuo to give 1.4 g (38%) of awhite solid.

¹H NMR; IS-MS, m/e 389.2 (m−1); Analysis for C₂₀H₂₆N₂O₆.0.4H₂O: Calcd:C, 60.41; H, 6.79; N, 7.05; Found: C, 60.27; H, 6.55; N, 6.92.

D.6-Acetyl-2-[(1-tert-butoxycarbonylpiperidin-4-yl)-4H-3,1-benzoxazin-4-one.

To a stirring solution of5-acetyl-2-[(1-tert-butoxycarbonylpiperidin-4-ylcarbonyl)amino]benzoicacid (0.22 g, 0.57 mmol) in N,N-dimethylformamide (3 mL) was added1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.14 g,0.74 mmol). The reaction solution was stirred for 30 min, treated withcold water and the resulting mixture stirred for 10 min and filtered togive 0.20 g (92%) of a tan solid.

¹H NMR; FD-MS, m/e 372.3 (m+1); Analysis for C₂₀H₂₄N₂O₅: Calcd: C,64.50; H, 6.50; N, 7.52; Found: C, 64.20; H, 6.40; N, 7.45.

E.5-Acetyl-2-[(1-tert-butoxycarbonylpiperidin-4-ylcarbonyl)amino]-N-(5-chloropyridin-2-yl)benzamide.

To an ice cold stirring solution of 2-amino-5-chloropyridine (0.11 g,0.86 mmol) in tetrahydrofuran (20 mL) was added dropwise a 1.0 Msolution of allylmagnesium bromide in diethyl ether (0.9 mL, 0.9 mmol).After stirring for 10 min,6-acetyl-2-[(1-tert-butoxycarbonylpiperidin-4-yl)-4H-3,1-benzoxazin-4-one(0.16 g, 0.43 mmol) was added. After stirring overnight at roomtemperature, the solvent was removed in vacuo. The residue waspartitioned between ethyl acetate and saturated aqueous sodium chloride,and layers were separated. The organic phase was washed with water,dried over magnesium sulfate, filtered, and concentrated in vacuo. Thecrude product was purified by chromatography, eluting with a stepgradient of 25-28% ethyl acetate in dichloromethane to give 155 mg (72%)of a white solid.

¹H NMR; IS-MS, m/e 501.3 (m+1), 499.2 (m−1); Analysis for C₂₅H₂₉ClN₄O₅:Calcd: C, 59.94; H, 5.83; N, 11.18; Found: C, 59.69; H, 6.03; N, 11.17.

F.5-Acetyl-N-(5-chloropyridin-2-yl)-2-[(4-piperidinylcarbonyl)amino]benzamideTrifluoroacetate.

Using methods substantially equivalent to those described in Example244-E,5-acetyl-N-(5-chloropyridin-2-yl)-2-[(piperidin-4-ylcarbonyl)amino]benzamidetrifluoroacetate (101 mg, 98%) was prepared from5-acetyl-2-[(1-tert-butoxycarbonylpiperidin-4-ylcarbonyl)amino]-N-(5-chloropyridin-2-yl)benzamide.

¹H NMR; IS-MS, m/e 401.2 (m+1), 399.2 (m−1); Analysis forC₂₀H₂₁Cl₂N₄O₃.1.2C₂HF₃O₂.0.1H₂O: Calcd: C, 49.87; H, 4.31; N, 10.39; F,12.68; Found: C, 49.89; H, 4.31; N, 10.48; F, 12.44.

G.5-Acetyl-N-(5-chloropyridin-2-yl)-2-[(1-isopropylpiperidin-4-ylcarbonyl)amino]benzamideHydrochloride.

Using methods substantially equivalent to those described in Example244-F,5-acetyl-N-(5-chloropyridin-2-yl)-2-(1-isopropylpiperidin-4-ylcarbonyl)amino]benzamidehydrochloride (48 mg, 67%) was prepared from5-acetyl-N-(5-chloropyridin-2-yl)-2-[(4-piperidinylcarbonyl)amino]-benzamidetrifluoroacetate. To a stirring solution of the purified product indichloromethane was added 1.0 N hydrochloric acid in diethyl ether untilprecipitate formed. The mixture was filtered to give the title compound.

¹H NMR; IS-MS, m/e 443.2 (m+1), 441.2 (m−1); Analysis forC₂₃H₂₇ClN₄O₃.1.3HCl.0.6H₂O: Calcd: C, 55.12; H, 5.93; N, 11.18; Cl,16.27; Found: C, 54.79; H, 6.32; N, 11.13; Cl, 16.30.

EXAMPLE 249 Preparation ofN-(5-Chloropyridin-2-yl)-2-[(1-isopropylpiperidin-4-ylcarbonyl)amino]-5-(2-thienyl)benzamideHydrochloride

Using methods substantially equivalent to those described in Example245,N-(5-chloropyridin-2-yl)-2-[(1-isopropylpiperidin-4-ylcarbonyl)amino]-5-(2-thienyl)benzamidehydrochloride (0.21 g, 42%) was prepared fromN-(5-chloropyridin-2-yl)-5-iodo-2-[(1-isopropylpiperidin-4-ylcarbonyl)amino]benzamide.

¹H NMR; IS-MS, m/e 482.9 (m+1), 480.9 (m−1); Analysis forC₂₅H₂₇ClN₄O₂S.2.0HCl.2.1H₂O: Calcd: C, 50.57; H, 5.64; N, 9.44; Cl,17.91; Found: C, 50.59; H, 5.46; N, 9.43; Cl, 17.85.

EXAMPLE 250 Preparation ofN-(5-chloropyridin-2-yl)-2-[(1-isopropylpiperidin-4-ylcarbonyl)amino]-5-(2-thiazolyl)benzamide

To a stirring solution ofN-(5-chloropyridin-2-yl)-5-iodo-2-[(1-isopropylpiperidin-4-ylcarbonyl)amino]benzamide(0.52 g, 0.99 mmol) and tetrakis(triphenylphosphine)palladium(0) (59 mg,0.05 mmol) in tetrahydrofuran (7 mL) was added a solution of 0.5 M2-thiazolezinc bromide (2.4 mL, 1.2 mmol) in tetrahydrofuran. Thereaction mixture was stirred overnight at room temperature and thendiluted with 3:1 chloroform:isopropanol. The resulting solution waswashed with saturated aqueous ammonium chloride and the phasesseparated. The aqueous phase was treated with saturated aqueous sodiumbicarbonate to pH 8 and extracted with 3:1 chloroform:isopropanol. Theorganic phase was dried over magnesium sulfate, filtered, andconcentrated in vacuo. The crude product was resubmitted to reactionconditions [tetrakis(triphenylphosphine)palladium(0) (38 mg, 0.03 mmol),tetrahydrofuran (7 mL), and a solution of 0.5 M 2-thiazolezinc bromide(9.6 mL, 4.8 mmol)], stirred overnight, and worked up as above. Thecrude product was purified by chromatography over silica gel, elutingwith a step gradient of 5-20% 2 M ammonia/methanol solution indichloromethane. The chromatography product was slurried in diethylether and filtered to give 0.27 g (57%) of a white solid.

¹H NMR; IS-MS, m/e 483.8 (m+1), 481.9 (m−1); Analysis forC₂₄H₂₆ClN₅O₂S.0.5H₂O: Calcd: C, 58.47; H, 5.52; N, 14.21; Found: C,58.16; H, 5.21; N, 14.04.

EXAMPLE 251 Preparation ofN-(5-Chloropyridin-2-yl)-2-[(1-isopropylpiperidin-4-ylcarbonyl)amino]-5-(3-pyridinyl)benzamide

Using methods substantially equivalent to those described in Example245,N-(5-chloropyridin-2-yl)-2-[(1-isopropylpiperidin-4-ylcarbonyl)amino]-5-(3-pyridinyl)benzamide(0.11 g, 24%) was prepared fromN-(5-chloropyridin-2-yl)-5-iodo-2-[(1-isopropylpiperidin-4-ylcarbonyl)amino]benzamideand 3-pyridyldiethylborate in tetrahydrofuran. The crude product waspurified by chromatography over silica gel, eluting with a step gradientof 10-15% 2 M ammonia/methanol solution in dichloromethane Thechromatography product was slurried in diethyl ether and filtered togive the title compound.

¹H NMR; IS-MS, m/e 477.9 (m+1), 475.9 (m−1); Analysis forC₂₆H₂₈ClN₅O₂.0.7H₂O: Calcd: C, 63.65; H, 6.04; N, 14.28; Found: C,63.32; H, 5.87; N, 14.29.

EXAMPLE 252 Preparation ofN-(5-Chloropyridin-2-yl)-2-[(1-isopropylpiperidin-4-ylcarbonyl)amino]-5-(4-pyridinyl)-benzamide

To a stirring solution ofN-(5-chloropyridin-2-yl)-5-iodo-2-[(1-isopropylpiperidin-4-ylcarbonyl)amino]benzamide(0.52 g, 0.98 mmol), dichlorobis(triphenylphosphine)palladium(II) (34mg, 0.05. mmol), and lithium chloride (0.15 g, 3.56 mmol) in 1,4-dioxane(5 mL) was added 4-(tributylstannyl)pyridine (1.16 g, 3.14 mmol) anddioxane (5 mL). The reaction mixture was heated to reflux, stirredovernight, and then filtered through diatomaceous earth. The filtratewas partitioned between 3:1 chloroform:isopropanol and saturated aqueoussodium bicarbonate, and the layers separated. The organic phase wasdried over magnesium sulfate, filtered, and concentrated in vacuo. Thecrude product was purified by chromatography over silica gel, elutingwith a step gradient of 10-25% 2 M ammonia/methanol solution indichloromethane. The chromatography product was recrystallized frommethanol and ethyl acetate to give 47 mg (10%) of a white solid.

¹H NMR; IS-MS, m/e 478.0 (m+1), 476.0 (m−1); Analysis forC₂₆H₂₈ClN₅O₂.1.6H₂O: Calcd: C, 61.62; H, 6.21; N, 13.82; Found: C,61.29; H, 5.87; N, 13.76.

EXAMPLE 253 Preparation ofN-(5-Chloropyridin-2-yl)-5-cyano-2-[(1-isopropylpiperidin-4-ylcarbonyl)amino]benzamide

To a stirring solution ofN-(5-chloropyridin-2-yl)-5-iodo-2-[(1-isopropylpiperidin-4-ylcarbonyl)amino]benzamide(0.50 g, 0.94 mmol) in N,N-dimethylformamide (6 mL) was added zinccyanide (70 mg, 0.58 mmol) followed bytetrakis(triphenylphosphine)palladium(0) (49 mg, 0.04 mmol). Thereaction mixture was stirred at 83° C. for 6 h and then at roomtemperature overnight. It was then partitioned between 3:1chloroform:isopropanol and ammonium hydroxide and the layers separated.The organic phase was dried over magnesium sulfate, filtered, andconcentrated in vacuo. The crude product was suspended in methanol andfiltered. The filtered solid was then slurried in diethyl ether andfiltered to give 70 mg (18%) of the title compound as white solid. Themethanolic filtrate was concentrated in vacuo and purified bychromatography over silica gel, eluting with 5-20% 2 M ammonia/methanolsolution in dichloromethane. The chromatography product was slurried inmethanol and filtered to give an additional 0.14 g (35%) of the titlecompound.

¹H NMR; IS-MS, m/e 426.0 (m+1), 424.0 (m−1); Analysis forC₂₂H₂₄ClN₅O₂.1.1H₂O: Calcd: C, 59.28; H, 5.92; N, 15.71; Found: C,58.91; H, 5.55; N, 15.72.

EXAMPLE 254 Preparation ofN-(5-Chloropyridin-2-yl)-5-(2-furanyl)-2-[(1-isopropylpiperidin-4-ylcarbonyl)amino]benzamide

Using methods substantially equivalent to those described in Example245,N-(5-chloropyridin-2-yl)-5-(2-furanyl)-2-[(1-isopropylpiperidin-4-ylcarbonyl)amino]benzamide(0.15 g, 34%) was prepared fromN-(5-chloropyridin-2-yl)-5-iodo-2-[(1-isopropylpiperidin-4-ylcarbonyl)amino]benzamide,2-(tributylstannyl)furan, anddichlorobis(triphenylphosphine)palladium(II) in tetrahydrofuran.

¹H NMR; IS-MS, m/e 466.9 (m+1), 464.9 (m−1); Analysis forC₂₅H₂₇ClN₄O₃.0.1H₂O: Calcd: C, 64.05; H, 5.85; N, 11.95; Found: C,63.83; H, 5.83; N, 11.93.

EXAMPLE 255 Preparation ofN-(5-Chloropyridin-2-yl)-2-[(1-isopropylpiperidin-4-ylcarbonyl)amino]-5-(2-pyridinyl)benzamide

Using methods substantially equivalent to those described in Example245,N-(5-chloropyridin-2-yl)-2-[(1-isopropylpiperidin-4-ylcarbonyl)amino]-5-(2-pyridinyl)benzamide(0.30 g, 65%) was prepared fromN-(5-chloropyridin-2-yl)-5-iodo-2-[(1-isopropylpiperidin-4-ylcarbonyl)amino]benzamideand 2-pyridylzinc bromide.

¹H NMR; IS-MS, m/e 477.9 (m+1), 475.9 (m−1); Analysis forC₂₆H₂₈ClN₅O₂.0.2H₂O: Calcd: C, 64.84; H, 5.94; N, 14.54; Found: C,64.67; H, 5.94; N, 14.22.

EXAMPLE 256 Preparation ofN-(5-Chloropyridin-2-yl)-2-[(1-isopropylpiperidin-4-ylcarbonyl)amino]-5-vinylbenzamide

To a stirring solution ofN-(5-chloropyridin-2-yl)-5-iodo-2-[(1-isopropylpiperidin-4-ylcarbonyl)amino]benzamide(1.0 g, 1.90 mmol) in N-methyl-2-pyrrolidinone (25 mL) was addedtetrakis(triphenylphosphine)palladium(0) (0.12 g, 0.1 mmol),triphenylarsine (60 mg, 0.2 mmol) and copper iodide (10 mg, 0.05 mmol)followed by tributyl(vinyl)tin (0.63 mL, 2.09 mmol). The reactionsolution was heated to 105° C., stirred for 8 h, partitioned betweendichloromethane and saturated aqueous sodium bicarbonate, and the layersseparated. The organic phase was washed with brine, dried over magnesiumsulfate, filtered, and concentrated in vacuo. The crude product waspurified by chromatography over silica gel, eluting with 10% 2 Mammonia/methanol solution in dichloromethane. The chromatography productwas slurried in methanol and filtered to give 131 mg (16%) of a whitesolid.

¹H NMR; IS-MS, m/e 427.1 (m+1), 425.1 (m−1); Analysis for C₂₃H₂₇ClN₄O₂:Calcd: C, 64.70; H, 6.37; N, 13.12; Found: C, 64.72; H, 6.51; N, 13.06.

EXAMPLE 257 Preparation ofN-(5-Chloropyridin-2-yl)-5-formyl-2-[(1-isopropylpiperidin-4-ylcarbonyl)amino]benzamideHydrochloride

To a stirring solution ofN-(5-chloropyridin-2-yl)-5-iodo-2-[(1-isopropylpiperidin-4-ylcarbonyl)amino]benzamide(0.51 g, 0.97 mmol) in N,N-dimethylformamide (10 mL) was added sodiumformate (0.11 g, 1.6 mmol), calcium sulfate (0.39 g, 2.9 mmol),triphenylphosphine (6 mg, 0.02 mmol) anddichlorobis(triphenylphosphine)palladium(II) (15 mg, 0.02 mmol). Thereaction mixture was heated to 80° C., stirred overnight, cooled to roomtemperature, partitioned between dichloromethane and saturated aqueoussodium bicarbonate, and the layers separated. The organic phase wasfiltered to remove solids, dried over magnesium sulfate, filtered, andconcentrated in vacuo. The crude product was purified by RPHPLC, elutingwith a gradient of 10% through 50% acetonitrile in 0.05% aqueoushydrochloric acid, to give 0.14 g (31%) of a yellow solid.

¹H NMR; IS-MS, m/e 428.9 (m+1), 426.9 (m−1); Analysis forC₂₂H₂₅ClN₄O₃.1.9HCl.2.0H₂O: Calcd: C, 49.46; H, 5.83; N, 10.49; Cl,19.25; Found: C, 49.51; H, 5.51; N, 10.39; Cl, 19.30.

EXAMPLE 258 Preparation ofN-(5-Chloropyridin-2-yl)-5-(1-hydroxyethyl)-2-[(1-isopropylpiperidin-4-ylcarbonyl)amino]benzamide

A.2-[(1-tert-Butoxycarbonylpiperidin-4-ylcarbonyl)amino]-N-(5-chloropyridin-2-yl)-5-(1-hydroxyethyl)benzamide.

To a stirring solution of5-acetyl-2-[(1-tert-butoxycarbonylpiperidin-4-ylcarbonyl)amino]-N-(5-chloropyridin-2-yl)benzamide(0.48 g, 0.96 mmol) in methanol (20 mL) was added sodium borohydride (36mg, 0.96 mmol). The reaction was stirred at room temperature for 5 min,treated with water, and concentrated in vacuo. The residual mixture waspartitioned between ethyl acetate and water and the layers separated.The organic phase was washed with brine, dried over magnesium sulfate,filtered, and concentrated in vacuo to give 0.47 g (98%) of a whitefoam.

¹H NMR; IS-MS, m/e 502.9 (m+1), 500.9 (m−1); Analysis for C₂₅H₃₁ClN₄O₅:Calcd: C, 59.70; H, 6.21; N, 11.14; Found: C, 53.77; H, 5.18; N, 10.77.

B.N-(5-Chloropyridin-2-yl)-5-(1-hydroxyethyl)-2-[(4-piperidinylcarbonyl)amino]benzamideTrifluoroacetate.

Using methods substantially equivalent to those described in Example244-E,N-(5-chloropyridin-2-yl)-5-(1-hydroxyethyl)]-2-[(4-piperidinylcarbonyl)amino]benzamidetrifluoroacetate (0.35 g, 86%) was prepared from2-[(1-tert-butoxycarbonylpiperidin-4-ylcarbonyl)amino]-N-(5-chloropyridin-2-yl)-5-(1-hydroxyethyl)benzamide.

¹H NMR; IS-MS, m/e 403.3 (m+1), 401.1 (m−1); Analysis forC₂₀H₂₃ClN₄O₃.1.6C₂HF₃O₂: Calcd: C, 47.61; H, 4.24; N, 9.57; F, 15.58;Found: C, 47.64; H, 3.96; N, 9.19; F, 16.91.

C.N-(5-Chloropyridin-2-yl)-5-(1-hydroxyethyl)-2-[(1-isopropylpiperidin-4-ylcarbonyl)amino]benzamide.

Using methods substantially equivalent to those described in Example244-F,N-(5-chloropyridin-2-yl)-5-(1-hydroxyethyl)-2-[(1-isopropylpiperidin-4-ylcarbonyl)amino]benzamide(0.15 g, 58%) was prepared fromN-(5-chloropyridin-2-yl)-5-(1-hydroxyethyl)-2-[(4-piperidinylcarbonyl)amino]benzamidetrifluoroacetate.

¹H NMR; IS-MS, m/e 445.2 (m+1), 443.3 (m−1); Analysis for C₂₃H₂₉ClN₄O₃:Calcd: C, 62.08; H, 6.57; N, 12.59; Found: C, 61.54; H, 5.42; N, 12.29.

EXAMPLE 260 Preparation of(E)-N-(5-Chloropyridin-2-yl)-2-[(1-isopropylpiperidin-4-ylcarbonyl)amino]-5-(2-methoxycarbonylvinyl)benzamide

A.(E)-2-[(1-tert-Butoxycarbonylpiperidin-4-ylcarbonyl)amino]-N-(5-chloropyridin-2-yl)-5-(2-methoxycarbonylvinyl)benzamide.

To a stirring solution of2-[(1-tert-butoxycarbonylpiperidin-4-ylcarbonyl)amino]-N-(5-chloropyridin-2-yl)-5-iodobenzamide(1.17 g, 2 mmol) in acetonitrile (4 mL) was added triethylamine (2 mL,14.3 mmol) followed by palladium(II) acetate (22 mg, 0.1 mmol) and thenmethyl acrylate (0.36 mL, 4 mmol). The mixture was heated to 100° C. ina sealed tube. After 15 h, the reaction mixture was cooled to roomtemperature and concentrated in vacuo. The crude product was purified bychromatography on silica gel, eluting with 20% ethyl acetate indichloromethane, to give 0.96 g (88%) of a white solid.

¹H NMR; IS-MS, m/e 543.2 (m+1), 541.4 (m−1); Analysis for C₂₇H₃₁ClN₄O₆:Calcd: C, 59.72; H, 5.75; N, 10.32; Found: C, 61.46; H, 5.97; N, 10.42.

B.(E)-N-(5-Chloropyridin-2-yl)-5-(2-methoxycarbonylvinyl)-2-[(4-piperidinylcarbonyl)amino]benzamideTrifluoroacetate.

Using methods substantially equivalent to those described in Example244-E,E-N-(5-chloropyridin-2-yl)-5-(2-methoxycarbonylvinyl)-2-[(4-piperidinylcarbonyl)amino]benzamidetrifluoroacetate (0.30 g, 98%) was prepared from(E)-2-[(1-tert-butoxycarbonylpiperidin-4-ylcarbonyl)amino]-N-(5-chloropyridin-2-yl)-5-(2-methoxycarbonylvinyl)benzamide.

¹H NMR; IS-MS, m/e 443.2 (m+1), 441.2 (m−1); Analysis forC₂₂H₂₃ClN₄O₄.1.0C₂HF₃O₂: Calcd: C, 51.76; H, 4.34; N, 10.06; F, 10.23;Found: C, 51.90; H, 4.17; N, 9.73; F, 10.93.

C.(E)-N-(5-Chloropyridin-2-yl)-2-[(1-isopropylpiperidin-4-ylcarbonyl)amino]-5-(2-methoxycarbonylvinyl)benzamide.

Using methods substantially equivalent to those described in Example244-F,(E)-N-(5-chloropyridin-2-yl)-2-[(1-isopropylpiperidin-4-ylcarbonyl)amino]-5-(2-methoxycarbonylvinyl)benzamide(92 mg, 42%) was prepared from(E)-N-(5-chloropyridin-2-yl)-5-(2-methoxycarbonylvinyl)]-2-[(4-piperidinylcarbonyl)amino]benzamidetrifluoroacetate.

¹H NMR; IS-MS, m/e 485.5 (m+1), 483.4 (m−1); Analysis forC₂₅H₂₉ClN₄O₄.0.1H₂O: Calcd: C, 61.68; H, 6.05; N, 11.51; Found: C,61.39; H, 6.13; N, 11.63.

EXAMPLE 260 Preparation of(E)-N-(5-Chloropyridin-2-yl)-5-(2-cyanovinyl)-2-[(1-isopropylpiperidin-4-ylcarbonyl)amino]benzamide

A.(E)-2-[(1-tert-Butoxycarbonylpiperidin-4-ylcarbonyl)amino]-N-(5-chloropyridin-2-yl)-5-(2-cyanovinyl)benzamide.

Using methods substantially equivalent to those described in Example259-A,2-[(1-tert-butoxycarbonylpiperidin-4-ylcarbonyl)amino]-N-(5-chloropyridin-2-yl)-5-iodobenzamidewas condensed with acrylonitrile. From the reaction mixture was isolated(E)-2-[(1-tert-butoxycarbonylpiperidin-4-ylcarbonyl)amino]-N-(5-chloropyridin-2-yl)-5-(2-cyanovinyl)benzamide(0.49 g, 48%), as well as the (Z)-isomer (see next example).

¹H NMR; IS-MS, m/e 510.2 (m+1), 508.2 (m−1); Analysis for C₂₆H₂₈ClN₅O₄:Calcd: C, 61.23; H, 5.53; N, 13.73; Found: C, 61.12; H, 5.79; N, 12.84.

B.(E)-N-(5-Chloropyridin-2-yl)-5-(2-cyanovinyl)]-2-[(4-piperidinylcarbonyl)amino]benzamideTrifluoroacetate.

Using methods substantially equivalent to those described in Example244-E,(E)-N-(5-chloropyridin-2-yl)-5-(2-cyanovinyl)-2-[(4-piperidinylcarbonyl)amino]benzamidetrifluoroacetate (0.20 g, 95%) was prepared from(E)-2-[(1-tert-butoxycarbonylpiperidin-4-ylcarbonyl)amino]-N-(5-chloropyridin-2-yl)-5-(2-cyanovinyl)benzamide.

¹H NMR; IS-MS, m/e 408.3 (m−1); Analysis for C₂₁H₂₀ClN₅O₂.1.1C₂HF₃O₂:Calcd: C, 52.05; H, 3.97; N, 13.08; F, 11.71; Found: C, 52.20; H, 4.13;N, 12.72; F, 11.47.

C.(E)-N-(5-Chloropyridin-2-yl)-5-(2-cyanovinyl)-2-[(1-isopropylpiperidin-4-ylcarbonyl)amino]benzamide.

Using methods substantially equivalent to those described in Example244-F,(E)-N-(5-chloropyridin-2-yl)-5-(2-cyanovinyl)-2-[(1-isopropylpiperidin-4-ylcarbonyl)amino]benzamide(48 mg, 36%) was prepared from(E)-N-(5-chloropyridin-2-yl)-5-(2-cyanoethenyl)-2-[(4-piperidinylcarbonyl)amino]benzamidetrifluoroacetate.

¹H NMR; IS-MS, m/e 452.2 (m+1), 450.1 (m−1); Analysis for C₂₄H₂₆ClN₅O₂:Calcd: C, 63.78; H, 5.80; N, 15.50; Found: C, 63.39; H, 5.84; N, 15.75.

EXAMPLE 261 Preparation of(Z)-N-(5-Chloropyridin.-2-yl)-5-(2-cyanovinyl)-2-[(1-isopropylpiperidin-4-ylcarbonyl)amino]benzamide

A.(Z)-2-[-tert-Butoxycarbonylpiperidin-4-ylcarbonyl)amino]-N-(5-chloropyridin-2-yl)-5-(2-cyanovinyl)]benzamide.

Using methods substantially equivalent to those described in Example259-A,2-[(1-tert-butoxycarbonylpiperidin-4-ylcarbonyl)amino]-N-(5-chloropyridin-2-y)-5-iodobenzamidewas condensed with acrylonitrile. From the reaction mixture was isolated(Z)-2-[(1-tert-butoxycarbonylpiperidin-4-ylcarbonyl)amino]-N-(5-chloropyridin-2-yl)-5-(2-cyanovinyl)benzamide(0.19 g, 19%), as well as the (E)-isomer (see prior example).

¹H NMR; IS-MS, m/e 510.3 (m+1), 508.2 (m−1); Analysis for C₂₆H₂₈ClN₅O₄:Calcd: C, 61.23; H, 5.53; N, 13.73; Found: C, 44.22; H, 4.08; N, 9.55.

B.(Z)-N-(5-Chloropyridin-2-yl)-5-(2-cyanovinyl)-2-[(4-piperidinylcarbonyl)amino]benzamideTrifluoroacetate.

Using methods substantially equivalent to those described in Example244-E,(Z)-N-(5-chloropyridin-2-yl)-5-(2-cyanovinyl)]-2-[(4-piperidinylcarbonyl)amino]benzamidetrifluoroacetate (0.13 g, 84%) was prepared from(Z)-2-[(1-tert-butoxycarbonylpiperidin-4-ylcarbonyl)amino]-N-(5-chloropyridin-2-yl)-5-(2-cyanovinyl)benzamide.

¹H NMR.

C.(Z)-N-(5-Chloropyridin-2-yl)-5-(2-cyanovinyl)-2-[(1-isopropylpiperidin-4-ylcarbonyl)amino]benzamide.

Using methods substantially equivalent to those described in Example244-F,(Z)-N-(5-chloropyridin-2-yl)-5-(2-cyanovinyl)-2-[(1-isopropylpiperidin-4-ylcarbonyl)amino]benzamide(41 mg, 46%) was prepared from(Z)-N-(5-chloropyridin-2-yl)-5-(2-cyanovinyl)-2-[(4-piperidinylcarbonyl)amino]benzamidetrifluoroacetate.

¹H NMR; IS-MS, m/e 452.2 (m+1), 450.1 (m−1).

EXAMPLE 262 Preparation ofN-(5-Chloropyridin-2-yl)-2-[(1-isopropylpiperidin-4-ylcarbonyl)amino]-5-methylthiobenzamide

A. N-(5-Chloropyridin-2-yl)-5-fluoro-2-nitrobenzamide.

Using methods substantially equivalent to those described in Example247-A, N-(5-chloropyridin-2-yl)-5-fluoro-2-nitrobenzamide (8.7 g, 70%)was prepared from 5-fluoro-2-nitrobenzoic acid and2-amino-5-chloropyridine.

¹H NMR; IS-MS, m/e 296.2 (m+1); Analysis for C₁₂H₇ClFN₃O₃: Calcd: C,48.75; H, 2.39; N, 14.21; Found: C, 48.96; H, 2.59; N, 14.02.

B. N-(5-Chloropyridin-2-yl)-5-methylthio-2-nitrobenzamide.

To a stirring solution of sodium methylsulfide (0.13 g, 2 mmol) inN,N-dimethylformamide (20 mL) was addedN-(5-chloropyridin-2-yl)-5-fluoro-2-nitrobenzamide (0.48 g, 1.6 mmol)and additional N,N-dimethylformamide (5 mL). The reaction solution wasstirred overnight at room temperature and concentrated in vacuo. Theresulting residue was partitioned between dichloromethane and water andthe layers separated. The organic phase was washed with saturatedaqueous sodium bicarbonate, dried over magnesium sulfate, filtered, andconcentrated in vacuo. The crude product was slurried in diethyl etherand filtered to give 0.33 g (63%) of a yellow solid.

¹H NMR; IS-MS, m/e 323.8 (m+1), 321.8 (m−1); Analysis for C₁₃H₁₀ClN₃O₃S:Calcd: C, 48.23; H, 3.11; N, 12.98; Found: C, 48.21; H, 3.01; N, 12.64.

C. 2-Amino-N-(5-chloropyridin-2-yl)-5-methylthiobenzamide.

To an argon-purged slurry ofN-(5-chloropyridin-2-yl)-5-methylthio-2-nitrobenzamide (0.78 g, 2.4mmol) in ethanol (30 mL) was added graphite (0.73 g) and hydrazinemonohydrate (0.5 mL, 10.3 mmol). The reaction mixture was heated toreflux, stirred overnight, cooled to room temperature, and filteredthrough diatomaceous earth. The filtrate was concentrated in vacuo togive 0.71 g (100%) of a yellow solid.

¹H NMR; IS-MS, m/e 294 (m+1), 291.9 (m−1); Analysis for C₁₃H₁₂ClN₃OS:Calcd: C, 53.15; H, 4.12; N, 14.30; Found: C, 52.34; H, 4.19; N, 13.87;and C, 52.36; H, 4.12; N, 13.44.

D.2-[(1-tert-Butoxycarbonylpiperidin-4-ylcarbonyl)amino]-N-(5-chloropyridin-2-yl)-5-methylthiobenzamide.

Using methods substantially equivalent to those described in Example244-D,2-[(1-tert-butoxycarbonylpiperidin-4-ylcarbonyl)amino]-N-(5-chloropyridin-2-yl)-5-methylthiobenzamide(0.96 g, 67%) was prepared from2-amino-N-(5-chloropyridin-2-yl)-5-methylthiobenzamide andBoc-isonipecotic acid.

¹H NMR; IS-MS, m/e 504.8 (m+1), 502.9 (m−1); Analysis for C₂₄H₂₉ClN₄O₄S:Calcd: C, 57.08; H, 5.79; N, 11.09; Found: C, 56.27; H, 4.82; N, 10.59;and C, 56.46; H, 4.80; N, 10.30.

E.N-(5-Chloropyridin-2-yl)-5-methylthio-2-[(4-piperidinylcarbonyl)amino]benzamideTrifluoroacetate.

Using methods substantially equivalent to those described in Example244-E,N-(5-chloropyridin-2-yl)-5-methylthio-2-[(4-piperidinylcarbonyl)amino]benzamidetrifluoroacetate (0.51 g, 96%) was prepared from2-[(1-tert-butoxycarbonylpiperidin-4-ylcarbonyl)amino]-N-(5-chloropyridin-2-yl)-5-methylthiobenzamide.

¹H NMR; IS-MS, m/e 404.9 (m+1), 402.9 (m−1); Analysis forC₁₉H₂₁ClN₄O₂S.1.0C₂HF₃O₂: Calcd: C, 48.60; H, 4.30; N, 10.76; Found: C,48.97; H, 4.40; N, 10.26.

F.N-(5-Chloropyridin-2-yl)-2-[(1-isopropylpiperidin-4-ylcarbonyl)amino]-5-methylthiobenzamide.

Using methods substantially equivalent to those described in Example244-F,N-(5-chloropyridin-2-yl)-2-[(1-isopropylpiperidin-4-ylcarbonyl)amino]-5-methylthiobenzamide(0.25 g, 74%) was prepared fromN-(5-chloropyridin-2-yl)-5-methylthio-2-[(piperidin-4-ylcarbonyl)amino]benzamidetrifluoroacetate.

¹H NMR; IS-MS, m/e 447.1 (m+1), 445.2 (m−1); Analysis forC₂₂H₂₇ClN₄O₂S.0.5H₂O: Calcd: C, 57.95; H, 6.19; N, 12.29; Found: C,57.76; H, 6.08; N, 12.20.

EXAMPLE 263 Preparation ofN-(5-Chloropyridin-2-yl)-2-[(1-isopropylpiperidin-4-ylcarbonyl)amino]-5-[1-(hydroxyimino)ethyl]benzamide

To a stirring solution of5-acetyl-N-(5-chloropyridin-2-yl)-2-[(1-isopropylpiperidin-4-ylcarbonyl)amino]benzamide(0.25 g, 0.56 mmol) in methanol (2 mL) was added sodium acetate (0.1 g,1.2 mmol) followed by hydroxylamine hydrochloride (46 mg, 0.67 mmol).The mixture was stirred overnight at room temperature and concentratedin vacuo. The resulting residue was partitioned between dichloromethaneand saturated aqueous sodium bicarbonate, and the layers separated. Theorganic phase was dried over magnesium sulfate, filtered, andconcentrated in vacuo. The crude product was purified by chromatographyover silica gel, eluting with 3% 2 M ammonia/methanol solution indichloromethane to give 0.22 g (85%) of a white solid.

¹H NMR; IS-MS, m/e 458.4 (m+1), 456.3 (m−1); Analysis for C₂₃H₂₈ClN₅O₃:Calcd: C, 60.32; H, 6.16; N, 15.29; Found: C, 54.52; H, 6.35; N, 16.62.

EXAMPLE 264 Preparation ofN-(5-Chloropyridin-2-yl)-5-hydroxymethyl-2-[(1-isopropylpiperidin-4-ylcarbonyl)amino]benzamide

A.2-[(1-tert-Butoxycarbonylpiperidin-4-ylcarbonyl)amino]-5-carboxy-N-(5-chloropyridin-2-yl)benzamide.

To a stirring solution of2-[(1-tert-butoxycarbonylpiperidin-4-ylcarbonyl)amino]-N-(5-chloropyridin-2-yl)-5-iodobenzamide(0.51 g, 0.88 mmol) in N,N-dimethylformamide (13 mL) under argon wasadded dichlorobis(triphenylphosphine)palladium(II) (28 mg, 0.04 mmol)and triethylamine (0.5 mL, 3.5 mmol) followed by water (3 mL). Thereaction mixture was evacuated and placed under an atmosphere of carbonmonoxide, heated at 60° C. for 3 h., and concentrated in vacuo. Theresulting residue was partitioned between aqueous sodium bicarbonate andethyl acetate and the layers separated. The aqueous phase was treatedwith a small amount of dichloromethane and then solid citric acid to pH3. The resulting mixture was extracted with 3:1 chloroform:isopropanol.The organic phase was dried over magnesium sulfate, filtered, andconcentrated in vacuo. The crude product was purified by chromatographyover silica gel, eluting with 2:4:0.5 ethyl acetate:toluene:acetic acid.The chromatography product was slurried in diethyl ether and filtered togive 0.31 g (69%) of a yellow solid.

¹H NMR; IS-MS, m/e 502.8 (m+1), 500.9 (m−1); Analysis for C₂₄H₂₇ClN₄O₆:Calcd: C, 57.31; H, 5.41; N, 11.14; Found: C, 55.96; H, 5.23; N, 10.64;and C, 56.84; H, 5.34; N, 10.91.

B.2-[(1-tert-Butoxycarbonylpiperidin-4-ylcarbonyl)amino]-N-(5-chloropyridin-2-yl)-5-hydroxymethylbenzamide.

To a stirring slurry of2-[(1-tert-butoxycarbonylpiperidin-4-ylcarbonyl)amino]-5-carboxy-N-(5-chloropyridin-2-yl)benzamide(0.25 g, 0.49 mmol) in tetrahydrofuran (5 mL) under argon was addedN-methylmorpholine (0.055 mL, 0.5 mmol) followed by ethyl chloroformate(0.05 mL, 0.5 mmol). After 20 min. the reaction slurry was cooled in anice bath and treated with sodium borohydride (61 mg, 1.6 mmol) followedby dropwise addition of methanol (10 mL). After 30 min the resultingreaction solution was treated with saturated aqueous ammonium chloride.The mixture was partitioned between dichloromethane and saturatedaqueous ammonium chloride. The organic phase was dried over magnesiumsulfate, filtered, and concentrated in vacuo. The crude product waspurified by chromatography over silica gel, eluting with 20-50% ethylacetate in hexane and then 5% methanol in ethyl acetate, to give 0.15 g(63%) of a white solid.

¹H NMR; IS-MS, m/e 488.9 (m+1), 486.9 (m−1); Analysis for C₂₄H₂₉ClN₄O₅:Calcd: C, 58.95; H, 5.98; N, 11.46; Found: C, 57.31; H, 5.86; N, 11.05;and C, 58.37; H, 5.86; N, 11.30.

C.N-(5-Chloropyridin-2-yl)-5-hydroxymethyl-2-[(4-piperidinylcarbonyl)amino]benzamideTrifluoroacetate.

Using methods substantially equivalent to those described in Example244-E,N-(5-chloropyridin-2-yl)-5-hydroxymethyl-2-[(4-piperidinylcarbonyl)amino]benzamidetrifluoroacetate (0.21 g, 96%) was prepared from2-[(1-tert-butoxycarbonylpiperidin-4-ylcarbonyl)amino]-N-(5-chloropyridin-2-yl)-5-hydroxymethylbenzamide.

¹H NMR; IS-MS, m/e 388.9 (m+1), 387.0 (m−1); Analysis forC₁₉H₂₁ClN₄O₃.1.2C₂HF₃O_(2.)0.5H₂O: Calcd: C, 48.07; H, 4.37; N, 10.48;F, 12.79; Found: C, 47.69; H, 4.05; N, 10.35; F, 12.71.

D.N-(5-Chloropyridin-2-yl)-5-hydroxymethyl-2-[(1-isopropylpiperidin-4-ylcarbonyl)amino]benzamide.

Using methods substantially equivalent to those described in Example244-F,N-(5-chloropyridin-2-yl)-5-hydroxymethyl-2-[(1-isopropylpiperidin-4-ylcarbonyl)amino]benzamide(0.11 g, 85%) was prepared fromN-(5-chloropyridin-2-yl)-5-hydroxymethyl-2-[(piperidin-4-ylcarbonyl)amino]benzamidetrifluoroacetate.

¹H NMR; IS-MS, m/e 431.0(m+1), 429.0 (m−1); Analysis for C₂₂H₂₇ClN₄O₃:Calcd: C, 61.32; H, 6.32; N, 13.00; Found: C, 61.53; H, 6.61; N, 12.83.

EXAMPLE 265 Preparation ofN-(5-Chloropyridin-2-yl)-2-[(1-isopropylpiperidin-4-ylcarbonyl)amino]-5-[2-(methoxycarbonyl)ethyl]benzamide

A.2-[(1-tert-Butoxycarbonylpiperidin-4-ylcarbonyl)amino]-N-(5-chloropyridin-2-yl)-5-[2-(methoxycarbonyl)ethyl]benzamide.

Using methods substantially equivalent to those described in Example244-B,2-[(1-tert-butoxycarbonylpiperidin-4-ylcarbonyl)amino]-N-(5-chloropyridin-2-yl)-5-[2-(methoxycarbonyl)ethyl]benzamide(44 mg, 45%) was prepared from(E)-2-[(1-tert-butoxycarbonylpiperidin-4-ylcarbonyl)amino]-N-(5-chloropyridin-2-yl)-5-[2-(methoxycarbonyl)vinyl)]benzamideand Raney nickel in 1:1 ethanol:ethyl acetate. The crude product waspurified by chromatography over silica gel, eluting with 50% ethylacetate in hexane.

¹H NMR; IS-MS, m/e 545.3 (m+1), 543.3 (m−1); Analysis for C₂₇H₃₃ClN₄O₆:Calcd: C, 59.50; H, 6.10; N, 10.28; Found: C, 59.05; H, 5.61; N, 10.07.

B.N-(5-Chloropyridin-2-yl)-5-[2-(methoxycarbonyl)ethyl]-2-[(4-piperidinylcarbonyl)amino]benzamideTrifluoroacetate.

Using methods substantially equivalent to those described in Example244-E,N-(5-chloropyridin-2-yl)-5-[2-(methoxycarbonyl)ethyl]-2-[(4-piperidinylcarbonyl)amino]-benzamidetrifluoroacetate (30 mg, 100%) was prepared from2-[(1-tert-butoxycarbonylpiperidin-4-ylcarbonyl)amino]-N-(5-chloropyridin-2-yl)-5-[2-(methoxycarbonyl)ethyl]benzamide.

C.N-(5-Chloropyridin-2-yl)-2-[(1-isopropylpiperidin-4-ylcarbonyl)amino]-5-[2-(methoxycarbonyl)ethyl]benzamide.

Using methods substantially equivalent to those described in Example244-F,N-(5-chloropyridin-2-yl)-2-[(1-isopropylpiperidin-4-ylcarbonyl)amino]-5-[1-(2-methoxycarbonylethyl)benzamide(20 mg, 77%) was prepared fromN-(5-chloropyridin-2-yl)-5-[1-(2-methoxycarbonylethyl)-2-[(4-piperidinylcarbonyl)amino]benzamidetrifluoroacetate. HPLC/MS, m/e 459.2 (m+1).

EXAMPLE 266 Preparation ofN-(5-Chloropyridin-2-yl)-2-[(1-isopropylpiperidin-4-ylcarbonyl)amino]-5-[1-(methoxyimino)ethyl]benzamide

Using methods substantially equivalent to those described in Example263,N-(5-chloropyridin-2-yl)-2-[(1-isopropylpiperidin-4-ylcarbonyl)amino]-5-[1-(methoxyimino)ethyl]benzamide(0.10 g, 67%) was prepared from5-acetyl-N-(5-chloropyridin-2-yl)-2-[(1-isopropylpiperidin-4-ylcarbonyl)amino]benzamide,methoxylamine hydrochloride and sodium acetate in methanol. The crudeproduct was purified by chromatography over silica gel, eluting with 5%2 M solution of ammonia/methanol in dichloromethane.

¹H NMR; IS-MS, m/e 472.3 (m+1), 470.3 (m−1); Analysis for C₂₄H₃₀ClN₅O₃:Calcd: C, 61.07; H, 6.41; N, 14.84; Found: C, 56.07; H, 6.45; N, 14.46.

EXAMPLE 267 Preparation ofN-(5-Chloropyridin-2-yl)-2-[(methyl)-[1-(4-pyridinyl)piperidin-4-ylmethyl]amino]benzamide

Using a similar procedure to that described in Example 27,N-(5-chloropyridin-2-yl)-2-[1-(4-pyridinyl)piperidin-4-ylmethyl]aminobenzamide(100 mg, 0.237 mmol) and paraformaldehyde (20 mg, 0.238 mmol) afforded,after purification by column chromatography (SiO₂: 2 to 4% [2 N ammoniain methanol]:chloroform), 25 mg (24%) of the title compound.

¹NMR; IS-MS, m/e 436 (m).

EXAMPLE 268 Preparation ofN-(5-Chloropyridin-2-yl)-2-[[1-(1-isopropylpiperidin-4-yl)ethyl]amino]-4-methoxycarbonylbenzamideTrihydrochloride

A. 1-(tert-Butoxycarbonyl)piperidine-4-ethanol

A solution of 1-(tert-butoxycarbonyl)piperidine-4-carboxaldehyde (14.9g, 69.8 mmol) in THF at −78° C. was treated with methylmagnesium bromide(25.6 mL, 3.0 M in THF, 76.8 mmol). After 16 h, the mixture was treatedwith additional methylmagnesium bromide (15.0 mL, 3.0 M in THF). After 1h, the mixture was treated with saturated aqueous ammonium chloride andpartitioned between EtOAc and water. The aqueous phase was washed withEtOAc, the organic extracts were combined and washed with brine, dried(MgSO₄), and concentrated. The residue was purified by columnchromatography (SiO₂: 30 to 40% EtOAc:hexanes) affording 5.0 g (31%) ofthe title compound.

¹NMR; IS-MS, m/e 230 (m+1).

B. 1-(tert-Butoxycarbonyl)piperidine-4-acetaldehyde

A solution of 1-(tert-butoxycarbonyl)piperidine-4-ethanol (5.0 g, 22mmol) in methylene chloride (100 mL) was treated with pyridiniumchlorochromate (5.2 g, 24 mmol), and diatomaceous earth (5 g). After 3days, the mixture was filtered through diatomaceous earth, concentrated,and the residue purified by column chromatography (SiO₂: 20 to 30%EtOAc:hexanes) affording 4.0 g (81%) of the title compound.

¹NMR; IS-MS, m/e 228 (m+1).

C.N-(5-Chloropyridin-2-yl)-2-[1-(1-boc-piperidin-4-yl)ethyl]amino]-4-methoxycarbonylbenzamide

Using a similar procedure to that described in Example 47-C,2-amino-N-(5-chloropyridin-2-yl)-4-methoxycarbonylbenzamide (2.7 g, 8.8mmol) and 1-(tert-butoxycarbonyl)piperidine-4-acetaldehyde (3.0 g, 13mmol) afforded, after trituration with EtOAc:methylene chloride, 2.8 g(61%) of the title compound.

¹NMR; IS-MS, m/e 513 (m−1); Analysis for C₂₆H₃₁ClN₄O₅: Calcd: C, 60.64;H, 6.07; N, 10.88; Found: C, 60.30; H, 6.26; N, 10.74.

D.N-(5-Chloropyridin-2-yl)-4-methoxycarbonyl-2-[[1-(4-piperidinyl)ethyl]amino]benzamide

Using a similar procedure to that described in Example 47-D,N-(5-chloropyridin-2-yl)-2-[[1-(1-Boc-piperidin-4-yl)ethyl]amino]-4-methoxycarbonylbenzamide(0.35 g, 0.68 mmol) and borane trimethylamine complex (0.15 g, 2.0 mmol)afforded 70 mg of the title compound. IS-MS, m/e 417 (m+1); Analysis forC₂₁H₂₅ClN₄O₃.2HCl: Calcd: C, 51.50; H, 5.56; N, 11.44; Found: C, 51.51;H, 5.73; N, 11.26.

E.N-(5-Chloropyridin-2-yl)-2-[[1-(1-isopropylpiperidin-4-yl)ethyl]amino]-4-methoxycarbonylbenzamideTrihydrochloride

Using a similar procedure to that described in Example 27,N-(5-chloropyridin-2-yl)-4-methoxycarbonyl-2-[[1-(4-piperidinyl)ethyl]amino]benzamide(0.35 g, 0.77 mmol) afforded, after purification by RPHPLC, 100 mg (26%)of the title compound as a hydrochloride salt.

¹NMR; IS-MS, m/e 459 (m+1); Analysis for C₂₄H₃₀ClN₄O₃.3HCl.1.5H₂O:Calcd: C, 48.42; H, 6.26; N, 9.41; Found: C, 48.49; H, 6.21; N, 9.55.

EXAMPLE 269 Preparation ofN-(5-Chloropyridin-2-yl)-4-hydroxymethyl-2-[(1-isopropylpiperidin-4-ylmethyl)amino]benzamideDihydrochloride

A.N-(5-Chloropyridin-2-yl)-4-hydroxymethyl-2-[(1-boc-piperidin-4-ylmethyl)amino]benzamide

Using a similar procedure to that described in Example 47-A,4-carboxy-N-(5-chloropyridin-2-yl)-2-[(1-Boc-piperidin-4-ylmethyl)amino]benzamide(2.0 g, 4.1 mmol), ethyl chloroformate (0.40 mL, 4.1 mmol),N-methylmorpholine (0.46 mL, 4.1 mmol), and sodium borohydride (466 mg,12.3 mmol) afforded 1.45 g (75%) of the title compound, which was usedwithout further purification.

¹NMR; IS-MS, m/e 473 (m+1); Analysis for C₂₂H₂₈ClN₅O₂: Calcd: C, 60.95;H, 6.18; N, 11.85; Found: C, 60.56; H, 6.25; N, 11.40.

B.N-(5-Chloropyridin-2-yl)-4-hydroxymethyl-2-[(4-piperidinylmethyl)amino]benzamide

Using a similar procedure to that described in Example 47-D,N-(5-chloropyridin-2-yl)-4-hydroxymethyl-2-[(1-Boc-piperidin-4-ylmethyl)amino]benzamide(1.45 g, 3.07 mmol) and borane trimethylamine complex (672 mg, 9.22mmol)afforded 900 mg (79%) of the title compound, which was used withoutfurther purification.

¹NMR; IS-MS, m/e 375 (m+1).

C.N-(5-Chloropyridin-2-yl)-4-hydroxymethyl-2-[(1-isopropylpiperidin-4-ylmethyl)amino]benzamidedihydrochloride

Using a similar procedure to that described in Example 27,N-(5-chloropyridin-2-yl)-4-hydroxymethyl-2-[(4-piperidinylmethyl)amino]benzamide(0.90 g, 2.4 mmol) afforded, after purification by RPHPLC, 630 mg (54%)of the title compound as a hydrochloride salt.

¹NMR; IS-MS, m/e 417 (m+1); Analysis for C₂₃H₃₀ClN₅O₂.2HCl.0.4H₂O:Calcd: C, 53.16; H, 6.45; N, 11.27; Found: C, 53.43; H, 6.23; N, 11.10.

EXAMPLE 270 Preparation ofN-(5-Chloropyridin-2-yl)-2-[(1-isopropylpiperidin-4-ylcarbonyl)amino]-4-methoxycarbonylbenzamide

A solution of 1-isopropylpiperidine-4-carboxylic acid (2.0 g, 9.6 mmol)in methylene chloride (70 mL) was treated dropwise with thionyl chloride(0.70 mL, 9.6 mmol). After heating to reflux for 1 h,2-amino-N-(5-chloropyridin-2-yl)-4-methoxycarbonylbenzamide (1.5 g, 4.8mmol) was added. After 0.5 h, pyridine (0.80 mL) was added and theresulting mixture heated at reflux. After 12 h, the mixture was cooled,treated with water, 1 N NaOH (20 mL), and concentrated. The residue waspurified by column chromatography (SiO₂: 5% methanol:methylene chloride)affording 1.14 g (52%) of the title compound.

¹NMR; FIA-MS, m/e 459 (m+); Analysis for C₂₄H₂₇ClN₄O₄.0.5H₂O: Calcd: C,59.03; H, 6.03; N, 11.97; Found: C, 59.31; H, 5.78; N, 11.91.

EXAMPLE 271 Preparation ofN-(5-Chloropyridin-2-yl)-2-[(1-isopropylpiperidin-4-ylcarbonyl)amino]-4-methoxycarbonylbenzamide

Using a similar procedure to that described in Example 275,1-(4-pyridinyl)piperidin-4-ylcarboxylic acid (2.0 g, 9.7 mmol), thionylchloride (1.4 m L, 19 mmol), and2-amino-N-(5-chloropyridin-2-yl)-4-methoxycarbonylbenzamide (2.8 g, 9.2mmol) afforded, after purification by column chromatography (SiO₂: 5 to10% [2.0 N ammonia in methanol]:methylene chloride), 0.40 g (9%) of thetitle compound.

¹NMR; FIA-MS, m/e 494 (m+); Analysis for C₂₅H₂₄ClN₅O₄: Calcd: C, 60.79;H, 4.90; N, 14.18; Found: C, 60.88; H, 4.90; N, 13.90.

EXAMPLE 272 Preparation ofN-(5-Chloropyridin-2-yl)-2-[(1-isopropylpiperidin-4-ylmethyl)amino]-5-methoxycarbonylbenzamide

A. N-(5-Chloropyridin-2-yl)-5-(methoxycarbonyl)-2-nitrobenzamide

Using a similar procedure to that described in Example 8-A,5-methoxycarbonyl-2-nitrobenzoic acid (20 g, 89 mmol) and2-amino-5-chloropyridine (11 g, 85 mmol) afforded, afterrecrystallization from toluene, 23.6 g (83%) of the title compound.

¹NMR; FIA-MS, m/e 336 (m+); Analysis for C₁₄H₁₀ClN₃O₅: Calcd: C, 50.09;H, 3.00; N, 12.52; Found: C, 50.37; H, 3.08; N, 12.52.

B. 2-Amino-N-(5-chloropyridin-2-yl)-5-methoxycarbonylbenzamide

Using a similar procedure to that described in Example 2-B,N-(5-chloropyridin-2-yl)-5-(methoxycarbonyl)-2-nitrobenzamide (23.5 g,70.0 mmol) afforded, after purification by column chromatography (1 to2% methanol:methylene chloride), 13.1 g (61%) of the title compound.

¹NMR; FIA-MS, m/e 306 (m+).

C. 1-Isopropylpiperidine-4-methanol

A solution of ethyl 1-isopropylpiperidine-4-carboxylate (10.0 g, 50.2mmol) in THF (250 mL) at 0° C. was treated with lithium aluminum hydride(2.1 g, 55 mmol). After 1 h, the mixture was treated with a saturatedaqueous solution of sodium potassium tartrate, partitioned with EtOAc,and the aqueous layer washed with EtOAc (2×). The combined extracts weredried (Na₂SO₄), concentrated, and the residue purified by columnchromatography (SiO₂: 10% methanol:methylene chloride) affording 4.30 g(54%) of the title compound.

¹NMR; FIA-MS, m/e 158 (m+).

D. 1-Isopropylpiperidine-4-carboxaldehyde

A solution of 1-isopropylpiperidine-4-methanol (0.40 g, 2.5 mmol) andN-methylmorpholine (0.46 g, 3.8 mmol) in methylene chloride (20 mL) wastreated with tetrapropylammonium perruthenate (0.089 g, 0.25 mmol).After 3 h, the mixture was concentrated and the residue purified bycolumn chromatography (SiO₂: 10% to 20% methanol:methylene chloride)affording 0.20 g (50%) of the title compound.

¹NMR; FIA-MS, m/e 156 (m+).

E.N-(5-Chloropyridin-2-yl)-2-[(1-isopropylpiperidin-4-ylmethyl)amino]-5-methoxycarbonylbenzamide

Using a similar procedure to that described in Example 47-C,2-amino-N-(5-chloropyridin-2-yl)-5-methoxycarbonylbenzamide (0.35 g, 1.2mmol) and 1-isopropylpiperidinecarboxaldehyde (0.20 g, 1.3 mmol)afforded, after purification by column chromatography (SiO₂: 10%methanol:methylene chloride), 150 mg (28%) of the title compound.

¹NMR; FIA-MS, m/e 443 (m+).

F.N-(5-Chloropyridin-2-yl)-2-[(1-isopropylpiperidin-4-ylmethyl)amino]-5-methoxycarbonylbenzamide

Using a similar procedure to that described in Example 47-D,N-(5-chloropyridin-2-yl)-2-[(1-isopropylpiperidin-4-ylmethyl)amino]-5-methoxycarbonylbenzamide(0.14 g, 0.32 mmol) and borane trimethylamine complex (0.70 g, 0.96mmol) afforded, after purification by column chromatography (SiO₂: 5 to10% methanol:methylene chloride), 110 mg (77%) of the title compound.

¹NMR; FIA-MS, m/e 445 (m+); Analysis for C₂₃H₂₇ClN₄O₄.0.5H₂O: Calcd: C,60.86; H, 6.66; N, 12.34; Found: C, 61.20; H, 6.31; N, 11.94.

EXAMPLE 273 Preparation of5-Carboxy-N-(5-chloropyridin-2-yl)-2-[(1-isopropylpiperidin-4-ylmethyl)amino]benzamideTrihydrochloride

A solution ofN-(5-chloropyridin-2-yl)-2-(1-isopropylpiperidin-4-ylmethyl)amino]-5-methoxycarbonylbenzamide(0.50 g, 1.1 mmol) in 1:1:1 methanol:THF:water was treated with bariumhydroxide octahydrate (3.6 g, 11 mmol). After 3 days, the mixture wastreated with 5 N HCl and concentrated under reduced pressure untilprecipitation resulted. The mixture was filtered affording 250 mg (52%)of the title compound as a hydrochloride salt.

¹NMR; FIA-MS, m/e 431 (m+); Analysis for C₂₂H₂₅ClN₄O₄.3.25HCl: Calcd: C,48.09; H, 5.55; N, 10.20; Found: C, 47.76; H, 5.59; N, 10.05.

EXAMPLE 274 Preparation ofN-(5-Chloropyridin-2-yl)-5-methoxycarbonyl-2-[[1-(4-pyridinyl)piperidin-4-ylmethyl]amino]benzamide

A.N-(5-Chloropyridin-2-yl)-5-methoxycarbonyl-2-[(4-piperidinylmethyl)amino]benzamide

Using a similar procedure to that described in Example 47-C&D,2-amino-N-(5-chloropyridin-2-yl)-5-methoxycarbonylbenzamide (3.23 g,10.6 mmol), 1-tert-butoxycarbonylpiperidine-4-carboxaldehyde (2.50 g,11.7 mmol), and borane trimethylamine complex (2.31 g, 31.7 mmol)afforded, after purification by column chromatography (SiO₂: 10 to 25%methanol:methylene chloride), 3.10 g (73%) of the title compound.

¹NMR; FIA-MS, m/e 403 (m+).

B.N-(5-Chloropyridin-2-yl)-5-methoxycarbonyl-2-[[1-(4-pyridinyl)piperidin-4-ylmethyl]amino]benzamide

Using a similar procedure to that described in Example 52,N-(5-chloropyridin-2-yl)-5-methoxycarbonyl-2-[(4-piperidinylmethyl)amino]benzamide(0.30 g, 0.74 mmol) and 4-chloropyridine hydrochloride (0.22 g, 1.5mmol) afforded, after purification by ion-exchange chromatography (SCX),260 mg (73%) of the title compound.

¹NMR; FIA-MS, m/e 480 (m+); Analysis for C₂₅H₂₆ClN₅O₃.0.45MeOH: Calcd:C, 61.83; H, 5.67; N, 14.17; Found: C, 62.19; H, 5.37; N, 13.76.

EXAMPLE 275 Preparation of5-Carboxy-N-(5-chloropyridin-2-yl)-2-[[1-(4-pyridinyl)piperidin-4-ylmethyl]amino]benzamide

Using a similar procedure to that described in Example 278,N-(5-chloropyridin-2-yl)-5-methoxycarbonyl-2-[[1-(4-pyridinyl)piperidin-4-ylmethyl]amino]benzamide(0.13 g, 0.26 mmol) afforded 105 mg (87%) of the title compound.

¹NMR; FIA-MS, m/e 466 (m+); Analysis for C₂₄H₂₄ClN₅O₃.0.75 H₂O: Calcd:C, 55.87; H, 5.18; N, 13.17; Found: C, 55.96; H, 5.10; N, 12.75.

EXAMPLE 276 Preparation ofN-(5-Chloropyridin-2-yl)-5-methoxycarbonyl-2-[[1-(2-carboxypyridin-4-yl)piperidin-4-ylmethyl]amino]benzamide

Using a similar procedure to that described in Example 52,N-(5-chloropyridin-2-yl)-5-methoxycarbonyl-2-[(4-piperidinylmethyl)amino]benzamide(0.30 g, 0.74 mmol) and 4-chloropicolinic acid (0.23 g, 1.5 mmol)afforded 320 mg (82%) of the title compound.

¹NMR; FIA-MS, m/e 524 (m+); Analysis for C₂₆H₂₆ClN₅O₅.1.85H₂O: Calcd: C,56.04; H, 5.37; N, 12.57; Found: C, 55.80; H, 4.98; N, 12.32.

EXAMPLE 277 Preparation ofN-(5-Chloropyridin-2-yl)-2-[[1-(2-cyanopyridin-4-yl)piperidin-4-ylmethyl]amino]-5-methoxycarbonylbenzamide

Using a similar procedure to that described in Example 52,N-(5-chloropyridin-2-yl)-5-methoxycarbonyl-2-[(4-piperidinylmethyl)amino]benzamide(0.30 g, 0.74 mmol) and 4-chloro-2-cyanopyridine (0.21 g, 1.5 mmol)afforded 360 mg (96%) of the title compound.

¹NMR; FIA-MS, m/e 505 (m+).

EXAMPLE 278 Preparation of2-(4-tert-Butylbenzoylamino)-N-(5-chloropyridin-2-yl)-4-methoxycarbonylbenzamide

A. 2-(4-tert-Butylbenzoyl)aminoterephthalic acid dimethyl ester.

Into 200 mL methylene chloride was dissolved 10.45g (50 mmol)2-aminoterephthalic acid dimethyl ester. The solution was cooled in anice bath, and 7.73 mL (55 mmol) triethylamine was added, followed by10.76 mL 4-tert-butylbenzoyl chloride in 50 mL methylene chloridedropwise. The mixture was allowed to come slowly to room temperature,and after 16 h the mixture was shaken with 200 mL cold dilute HCl and200 mL satd NaHCO₃. The organic layer was dried (MgSO₄) and evaporated.The residue was redissolved in a minimum ether, giving 13.5 g (73%) ofcrystalline desired intermediate.

¹NMR, MS.

B. 2-(4-tert-Butylbenzoylamino)terephthalic Acid.

Into 100 mL MeOH was dissolved 5.0 g (13.6 mmol) of the above dimethylester, followed by 13.6 mL (68 mmol) 5 N NaOH. The mixture was stirred 4h at room temperature, concentrated under vacuum, acidified with diluteHCl and extracted with 200 mL EtOAc. Organic layer was dried (MgSO₄),concentrated under vacuum, and diluted with hexane, giving 2.59 g (56%)crystalline desired intermediate.

¹NMR, MS.

C. 2-(4-tert-Butylphenyl)-7-methoxycarbonyl-4H-3,1-benzoxazin-4-one.

Into 50 mL methylene chloride was dissolved 0.682 g (2 mmol) of theabove intermediate terephthalic acid, followed by 5 drops DMF and 3.88mL (48 mmol) triethylamine The mixture was cooled in an ice bath, and0.42 mL (4.8 mmol) oxayl chloride was added in one portion. After 30 min10 mL MeOH was added and ice bath was removed. After stirring anadditional 30 min, the mixture was shaken between EtOAc (100 mL) andcold dilute HCl (100 mL). The organic layer was washed with satd NaHCO₃(100 mL), dried (MgSO₄), and evaporated. Crystalline desiredbenzoxazinone (456 g, 66%) was obtained from a concentrated methylenechloride-hexane solution.

¹NMR, MS.

D.2-(4-tert-Butylbenzoylamino)-N-(5-chloropyridin-2-yl)-4-methoxycarbonylbenzamide.

Into 25 mL THF was dissolved 0.174 g (0.5 mmol) of the aboveintermediate benzoxazinone. The solution was cooled in an ice bath, and1.25 mL (0.5 mmol) of a 0.5 M THF solution of the magnesium salt of2-amino-5-chloropyridine [prepared by treating 1.29 g (10 mmol)2-amino-5-chloropyridine in 22 mL THF at ice bath temperature undernitrogen with 3.3 mL (10 mmol) 3 M methylmagnesium bromide, allowing themixture to slowly come to room temperature]. After 30 min, 0.42 mL (0.17mmol) of additional magnesium salt was added, and the mixture wasstirred an additional 15 min. The mixture was quenched with 30 mL colddilute HCl and extracted with 100 mL EtOAc. The organic layer was dried(MgSO₄) and evaporated. The crystalline title compound was obtained (107mg, 46%) from CH₂Cl₂-hexane.

NMR, MS.

EXAMPLE 279 Preparation of2-(4-tert-Butylbenzoylamino)-4-carbonoxy-N-(5-chloropyridin-2-yl)benzamide.

Into 2 mL MeOH was dissolved 103 mg (0.22 mmol)2-(4-tert-butylbenzoylamino)-N-(5-chloropyridin-2-yl)-4-methoxycarbonylbenzamideTo the solution was added 0.53 mL (0.27 mmol)of 0.5 N NaOH. The mixturewas stirred 16 h at room temperature, diluted with 25 mL water andextracted with 50 mL EtOAc. The aquous layer was acidified with diluteHCl and extracted with 50 mL EtOAc. Organic layer was dried (MgSO₄), andevacuated, giving 32 mg (32%) of the title compound.

¹NMR, MS.

EXAMPLE 280 Preparation of2-(4-tert-Butylbenzoylamino)-N-(5-chloropyridin-2-yl)-5-methoxycarbonylbenzamide.

A. 4-Aminoisophthalic Acid

Into 20 mL EtOH and 20 mL HOAc was dissolved 2 g (9.48 mmol)4-nitroisophthalic acid, and the solution was subjected to hydrogenationat atmospheric conditions over 1 g of 5% Pd on carbon. After 16 h,mixture was filtered, and filtrate was evaporated. The residuecrystallized from methylene chloride-hexane, giving 1.29 g (75%)crystalline desired intermediate.

¹NMR, MS.

B. 4-(4-tert-Butylbenzoylamino)isophthalic Acid

Into 60 mL acetone was dissolved 0.905 g (5 mmol) 4-aminoisophthalicacid. To the solution was added 30 mL water. The mixture was cooled inan ice bath, and 1.08 mL (5.5 mmol) 4-tert-butylbenzoyl chloride in 10mL acetone was added dropwise. The mixture was allowed to warm slowlylyto room temperature and after 24 h was concentrated under vacuum andshaken between EtOAc (150 mL) and cold dilute HCl (150 mL). The organiclayer was dried (MgSO₄) and evaporated. The desired crystalline product(0.489 g, 29%) was obtained from methylene chloride-hexane.

¹NMR, MS.

C. 2-(4-tert-Butylphenyl)-6-methoxycarbonyl-4H-3,1-benzoxazin-4-one.

Into 25 mL methylene chloride was dissolved 0.341 g (1 mmol) of theabove intermediate isophthalic acid, followed by 2 drops DMF and 1.94 mL(24 mmol) pyridine. The mixture was cooled in an ice bath, and 0.21 mL(2.4 mmol) oxayl chloride was added. The mixture was stirred 30 min, 5mL MeOH added, and the ice bath was removed. The mixture was stirred anadditional 30 min, shaken between CH₂Cl₂ (100 mL) and cold dilute HCl(100 mL). The organic layer was washed with satd NaHCO₃ (100 mL), dried(MgSO₄), and concentrated under vacuum. Crystalline desired product (184mg, 53%) was obtained from CH₂Cl₂-hexane.

¹NMR, MS.

D.2-(4-tert-Butylbenzoylamino)-N-(5-chloropyridin-2-yl)-5-methoxycarbonylbenzamide

Into 25 mL THF was dissolved 0.174 g (0.5 mmol) of the abovebenzoxazinone intermediate. The solution was cooled in an ice bath andplaced under nitrogen atmosphere. To the mixture was added 1.5 mL (0.6mmol) of a 0.4 M solution of the magnesium salt of2-amino-5-chloropyridine (See Prep. D, Example 278). After 30 min, anadditional 1.5 mL (0.6 mmol) of the magnesium salt was added. Stirringwas continued for 15 min, and the reaction mixture was quenched with 100mL cold dilute HCl. The mixture was extracted with 100 mL EtOAc, and theorganic layer was washed with 100 mL cold dilute HCl, dried (MgSO₄), andconcentrated under vacuum. The crude product was chromatographed oversilica (0 to 30% EtOAc in hexane gradient), giving 91 mg (39%) of titlecompound as a crystalline solid.

¹NMR, MS.

EXAMPLE 281 Preparation of4-(4-tert-Butylbenzoylamino)-N-(5-chloropyridin-2-yl)isophthalamic Acid

Into 5 mL MeOH was dissolved 91 mg (0.195 mmol)2-(4-tert-butylbenzoylamino)-N-(5-chloropyridin-2-yl)-5-methoxycarbonylbenzamide,followed by 0.47 mL of 0.5 N (0.23 mmol) NaOH. The mixture was stirred16 h, evaporated, diluted with 39.0 mL water, and extracted with 15 mLEtOAc-15 mL hexane mixture. The aquous layer was acidified with diluteHCl and extracted with 30 mL EtOH. The organic layer was dried (MgSO₄)and evaporated, giving 43 mg (.49%) title compound.

¹NMR, MS.

1 1 4 PRT Artificial Sequence Chromogenic Substrate for Factor Xa 1 IleGlu Gly Arg 1

What is claimed is:
 1. A compound of formula I

(or a pharmaceutically acceptable salt thereof) wherein: A³, A⁴, A⁵ andA⁶, together with the two carbons to which they are attached, complete asubstituted benzene in which A³ is CR³, A⁴ is CR⁴, A⁵ is CR⁵, and A⁶ isCR⁶; wherein R³ is hydrogen, methyl, methoxy, fluoro, chloro or carboxy;one of R⁴ and R⁵ is hydrogen, (1-4C)alkyl, halo, trifluoromethyl,trifluoromethoxy, R^(f)O—, R^(f)O₂CCH₂O—, HO(CH₂)_(a)O— (in which a is2, 3 or 4), R^(f)O₂C—, R^(f)O₂CCH₂—, R^(g)NH—, R^(h)SO₂—, hydroxymethyl,formyl, cyano, acetyl, 1-hydroxyethyl, 1-(hydroxyimino)ethyl,1-(methoxyimino)ethyl, methylthio or R^(f)O₂C(CH₂)₂—; the other of R⁴and R⁵ is hydrogen; and R⁶ is hydrogen, methyl, fluoro, chloro ormethoxy; in which R^(f) is hydrogen, (1-4C) alkyl or benzyl; R^(g) ishydrogen or R^(h)SO₂—; and R^(h) is (1-4C)alkyl or dimethylamino; oreach of R³, R⁴ and R⁶ is hydrogen; and R⁵ is vinyl, 2-cyanovinyl,2-({(1-2C)alkoxy}carbonyl)vinyl or R^(a) in which R^(a) is phenyl (whichis unsubstituted or bears one or more substituents independentlyselected from halo, methyl, methoxy and hydroxy) or heteroaryl (whichheteroaryl is a 5-membered aromatic ring which has one to fourheteroatoms selected from sulfur, oxygen and nitrogen or is a 6-memberedaromatic ring which has one to three nitrogen atoms, wherein theheteroaryl is attached at carbon and may bear one or more methylsubstituents on carbon or nitrogen); L¹ is —CO—NH— such that —L¹—Q¹ is—CO—NH—Q¹; Q¹ is 2-pyridinyl (which bears a methyl, methoxy, methylthio,fluoro or chloro substituent at the 5-position), or 3-pyridinyl (whichbears a methyl, fluoro or chloro substituent at the 6-position); R² is—L²—Q² in which —L²— is —NH—CO—, —NH—CO—X—, —NH—CO—O—X—, —NH—CO—NH—X—,—NH—CH₂—, —NH—C(CH₃)H—, —N(CH₃)—CH₂— or —O—CH₂—; and Q² is Q^(2A),Q^(2B), Q^(2C), Q^(2D), Q^(2E) or Q^(2F) wherein X is a single bond ormethylene and the values of L² and Q² are together selected from—NH—CO—X—Q^(2A), —NH—CO—O—X—Q^(2A), —NH—CO—NH— X—Q^(2A), —NH—CH₂—Q^(2A),—NH—C(CH₃)H—Q^(2A), —N(CH₃)—CH₂—Q², —O—CH₂—Q^(2A), —NH—CO—X—Q^(2B),—NH—CO—Q^(2C), —NH—CO—Q^(2D), —NH—CO—Q^(2E) and —NH—CO—Q^(2F) in which:Q^(2A) (showing the L² to which it is attached) is

 in which each of m and n independently is 0 or 1, or m is 2 and n is 1,and R^(2A) is hydrogen, t-butyl, methylsulfonyl, —CHR^(y)R^(z),—CHR^(w)R^(x), or 4-pyridinyl (which is unsubstituted or bears asubstituent R^(v) at the 2- or 3-position) wherein R^(v) is methyl,hydroxymethyl, {(1-2C)alkoxy}carbonyl; cyano, carbamoyl, thiocarbamoyl,or N-hydroxyamidino; each of R^(w) and R^(x) independently is hydrogenor (1-3C)normal alkyl; or —CHR^(w)R^(x) is 2-indanyl or (showing thenitrogen to which it is attached) is

 in which T is a single bond or methylene and U is methylene, ethylene,oxy, —S(O)_(q)— (wherein q is 0, 1 or 2) or imino (which may bear amethyl substituent), or T is ethan-1,1-diyl and U is a single bond ormethylene; R^(y) is hydrogen or methyl; and R^(z) is isopropyl, t-butyl,(3-6C)cycloalkyl, phenyl (which is unsubstituted or bears one or moresubstituents independently selected from halo, methyl, methoxy andhydroxy), 4-quinolinyl or heteroaryl (which heteroaryl is a 5-memberedaromatic ring which has one to four heteroatoms selected from sulfur,oxygen and nitrogen or is a 6-membered aromatic ring which has one tothree nitrogen atoms, wherein the heteroaryl is attached at carbon andmay bear one or more methyl substituents on carbon or nitrogen); orR^(2A) is —L^(b)—CH₂—R^(b) in which —L^(b)— is a direct bond, —CH₂—,—C(CH₃)H— or —CH₂—CH₂—; and R^(b) is carboxy, {(1-2C)alkoxy}carbonyl,cyano, carbamoyl or trifluoromethyl; or R^(2A) is —CO—R^(c) in whichR^(c) is hydrogen, (1-3C)alkyl, {(1-2C)alkoxy}carbonyl-(CH₂)_(c)— (inwhich c is 1 or 2), phenyl (which is unsubstituted or bears one or moresubstituents independently selected from halo, methyl, methoxy andhydroxy), heteroaryl (which heteroaryl is a 5-membered aromatic ringwhich has one to four heteroatoms selected from sulfur, oxygen andnitrogen or is a 6-membered aromatic ring which has one to threenitrogen atoms, wherein the heteroaryl is attached at carbon and maybear one or more methyl substituents on carbon or nitrogen) or—NR^(d)R^(e) in which each of R^(d) and R^(e) is independently hydrogen,methyl or ethyl, or —NR^(d)R^(e) is pyrrolidino, piperidino, morpholinoor thiomorpholino; Q^(2B) is 1-piperazinyl which bears at the 4-positionthe group R^(2A) (defined as above); Q^(2C) is3,4-didehydropiperidin-4-yl which bears at the 1-position the groupR^(2A) (defined as above); Q^(2D) is cyclohexyl which bears at the4-position the group —NR^(s)R^(t) in which each of R^(s) and R^(t)independently is hydrogen or methyl or R^(s) and R^(t) together aretrimethylene or tetramethylene; Q^(2E) is 1-piperidinyl which bears atthe 4-position the group —NR^(s)R^(t) (defined as above); and Q^(2F)(showing the L² to which it is attached) is

 in which R^(o) is hydrogen, halo, (1-6C)alkyl, hydroxy, (1-4C)alkoxy,benzyloxy or (1-4C)alkylthio; and R^(p) is acetylamino, 1-hydroxyethyl,1-hydroxy-1-methylethyl, 1-methoxy-1-methylethyl, 4-piperidinyl,4-pyridinyl, dimethylaminosulfonyl or —J—R^(q) in which J is a singlebond, methylene, carbonyl, oxy, —S(O)_(q)— (wherein q is 0, 1 or 2), or—NR^(r)— (wherein R^(r) is hydrogen or methyl); and R^(q) is(1-6C)alkyl, phenyl, 3-pyridyl or 4-pyridyl; or —NR^(q)R^(r) ispyrrolidino.
 2. The compound of formula I as claimed in claim 1

(or a pharmaceutically acceptable salt thereof) wherein: A³, A⁴, A⁵ andA⁶, together with the two carbons to which they are attached, complete asubstituted benzene in which A³ is CR³, A⁴ is CR⁴, A⁵ is CR⁵, and A⁶ isCR⁶; wherein R³ is hydrogen, methyl, fluoro, chloro or carboxy; one ofR⁴ and R⁵ is hydrogen, (1-4C)alkyl, halo, trifluoromethyl,trifluoromethoxy, R^(f)O—, R^(f)O₂CCH₂O—, HO(CH₂)_(a)— (in which a is 2,3 or 4), R^(f)O₂C—, R^(f)O₂CCH₂—, R^(g)NH— or R^(h)SO₂—; the other of R⁴and R⁵ is hydrogen; and R⁶ is hydrogen, methyl, fluoro, chloro ormethoxy; in which R^(f) is hydrogen, (1-4C)alkyl or benzyl; R^(g) ishydrogen or R^(h)SO₂—; and R^(h) is (1-4C)alkyl or dimethylamino; L¹ is—CO—NH— such that —L¹—Q¹ is —CO—NH—Q¹; Q¹ is 2-pyridinyl (which bears amethyl, methoxy, methylthio, fluoro or chloro substituent at the5-position), or 3-pyridinyl (which bears a methyl, fluoro or chlorosubstituent at the 6-position); R² is —L²—Q² in which —L²— is —NH—CO—,—NH—CO—X—, —NH—CO—O—X—, —NH—CO—NH—X—, —NH—CH₂— or —O—CH₂—; and Q² isQ^(2A), Q^(2B), Q^(2C), Q^(2D), Q^(2E) or Q^(2F) wherein X is a singlebond or methylene and the values of L² and Q² are together selected from—NH—CO—X—Q^(2A), —NH—CO—O—X—Q^(2A), —NH—CO—NH—X—Q^(2A), —NH—CH₂—Q^(2A),—O—CH₂—Q^(2A), —NH—CO—X—Q^(2B), —NH—CO—Q^(2C), —NH—CO—Q^(2D),—NH—CO—Q^(2E) and —NH—CO—Q^(2F) in which: Q^(2A) (showing the L² towhich it is attached) is

 in which each of m and n independently is 0 or 1, and R^(2A) ishydrogen, t-butyl, methylsulfonyl, —CHR^(y)R^(z), —CHR^(w)R^(x), or4-pyridinyl (which is unsubstituted or bears a substituent R^(v) at the2- or 3-position) wherein R^(v) is methyl, hydroxymethyl,{(1-2C)alkoxy}carbonyl; cyano, carbamoyl, thiocarbamoyl, orN-hydroxyamidino; each of R^(w) and R^(x) independently is hydrogen or(1-3C)normal alkyl; or —CHR^(w)R^(x) is 2-indanyl or (showing thenitrogen to which it is attached) is

 in which T is a single bond or methylene and U is methylene, ethylene,oxy, —S(O)_(q)— (wherein q is 0, 1 or 2) or imino (which may bear amethyl substituent), or T is ethan-1,1-diyl and U is a single bond ormethylene; R^(Y) is hydrogen or methyl; and R^(z) is isopropyl, t-butyl,(3-6C)cycloalkyl, phenyl (which is unsubstituted or bears one or moresubstituents independently selected from halo, methyl, methoxy andhydroxy), 4-quinolinyl or heteroaryl (which heteroaryl is a 5-memberedaromatic ring which has one to four heteroatoms selected from sulfur,oxygen and nitrogen or is a 6-membered aromatic ring which has one tothree nitrogen atoms, wherein the heteroaryl is attached at carbon andmay bear one or more methyl substituents on carbon or nitrogen); Q^(2B)is 1-piperazinyl which bears at the 4-position the group R^(2A) (definedas above); Q^(2C) is 3,4-didehydropiperidin-4-yl which bears at the1-position the group R^(2A) (defined as above); Q^(2D) is cyclohexylwhich bears at the 4-position the group —NR^(s)R^(t) in which each ofR^(s) and R^(t) independently is hydrogen or methyl or R^(s) and R^(t)together are trimethylene or tetramethylene; Q^(2E) is 1-piperidinylwhich bears at the 4-position the group —NR^(s)R^(t) (defined as above);and Q^(2F) (showing the L² to which it is attached) is

 in which R^(o) is hydrogen, halo, (1-6C)alkyl, hydroxy, (1-4C)alkoxy,benzyloxy or (1-4C)alkylthio; and R^(p) is acetylamino, 1-hydroxyethyl,1-hydroxy-1-methylethyl, 1-methoxy-1-methylethyl, 4-piperidinyl,4-pyridinyl, dimethylaminosulfonyl or —J—R^(q) in which J is a singlebond, methylene, carbonyl, oxy, —S(O)_(q)— (wherein q is 0, 1 or 2), or—NR^(r)— (wherein R^(r) is hydrogen or methyl); and R^(q) is(1-6C)alkyl, phenyl, 3-pyridyl or 4-pyridyl.
 3. A compound of formula I(or a pharmaceutically acceptable salt thereof) as claimed in claim 2wherein: A³, A⁴, A⁵ and A⁶, together with the two carbons to which theyare attached, complete a substituted benzene in which A³ is CR³, A⁴ isCR⁴, A⁵ is CR⁵, and A⁶ is CR⁶; wherein R³ is hydrogen; one of R⁴ and R⁵is hydrogen, methyl, fluoro, chloro, trifluoromethyl, trifluoromethoxy,R^(f)O₂C— or R^(g)NH—; the other of R⁴ and R⁵ is hydrogen; and R⁶ ishydrogen; in which R^(f) is hydrogen, (1-4C)alkyl or benzyl; R^(g) ishydrogen or R^(h)SO₂—; and R^(h) is (1-4C)alkyl or dimethylamino; L¹ is—CO—NH— such that —L¹—Q¹ is —CO—NH—Q¹; Q¹ is 2-pyridinyl (which bears amethyl, fluoro or chloro substituent at the 5-position), or 3-pyridinyl(which bears a methyl, fluoro or chloro substituent at the 6-position);R² is —L²—Q² in which —L²— is —NH—CO—, —NH—CO—X—, —NH—CO—O—X—,—NH—CO—NH—X—, —NH—CH₂— or —O—CH₂—; and Q² is Q^(2A), Q^(2B), Q^(2C),Q^(2D), Q^(2E) or Q^(2F) wherein X is a single bond or methylene and thevalues of L² and Q² are together selected from —NH—CO—X—Q^(2A),—NH—CO—O—X—Q^(2A), —NH—CO—NH—X—Q^(2A), —NH—CH₂—Q^(2A), —O—CH₂—Q^(2A),—NH—CO—X—Q^(2B), —NH—CO—Q^(2C), —NH—CO—Q^(2D), —NH—CO—Q^(2E) and—NH—CO—Q^(2F) in which: Q^(2A) (showing the L² to which it is attached)is

 in which each of m and n independently is 0 or 1, and R^(2A) ishydrogen, —CHR^(y)R^(z), —CHR^(w)R^(x), or 4-pyridinyl (which isunsubstituted or bears a substituent R^(v) at the 2- or 3-position)wherein R^(v) is methyl, hydroxymethyl, {(1-2C)alkoxy}carbonyl; cyano,carbamoyl, thiocarbamoyl, or N-hydroxyamidino; each of R^(w) and R^(x)independently is hydrogen or (1-3C)normal alkyl; or —CHR^(w)R^(x) is2-indanyl or (showing the nitrogen to which it is attached) is

 in which T is a single bond or methylene and U is methylene, oxy,thioxy or imino (which may bear a methyl substituent), or T isethan-1,1-diyl and U is a single bond or methylene; R^(y) is hydrogen ormethyl; and R^(z) is isopropyl, t-butyl, (3-6C)cyclopropyl, phenyl(which is unsubstituted or bears one or more substituents independentlyselected from halo, methyl, methoxy and hydroxy), 4-quinolinyl orheteroaryl (which heteroaryl is a 5-membered aromatic ring which has oneto four heteroatoms selected from sulfur, oxygen and nitrogen or is a6-membered aromatic ring which has one to three nitrogen atoms, whereinthe heteroaryl is attached at carbon and may bear one or more methylsubstituents on carbon or nitrogen); Q^(2B) is 1-piperazinyl which bearsat the 4-position the group R^(2A) (defined as above); Q^(2C) is3,4-didehydropiperidin-4-yl which bears at the 1-position the groupR^(2A) (defined as above); Q^(2D) is cyclohexyl which bears at the4-position the group —NR^(s)R^(t) in which each of R^(s) and R^(t)independently is hydrogen or methyl or R^(s) and R^(t) together aretrimethylene or tetramethylene; Q^(2E) is 1-piperidinyl which bears atthe 4-position the group —NR^(s)R^(t) (defined as above); and Q^(2F)(showing the L² to which it is attached) is

 in which R^(o) is hydrogen and R^(p) is acetylamino, 1-hydroxyethyl,1-hydroxy-1-methylethyl, 1-methoxy-1-methylethyl, 4-piperidinyl,4-pyridinyl, dimethylaminosulfonyl or —J—R^(q) in which J is a singlebond, methylene, carbonyl, oxy, —S(O)_(q)— (wherein q is 0, 1 or 2), or—NR^(r)— (wherein R^(r) is hydrogen or methyl); and R^(q) is(1-6C)alkyl, phenyl, 3-pyridyl or 4-pyridyl.
 4. The compound of claim 1,2 or 3 wherein halo is fluoro, chloro, bromo or iodo; (1-2C)alkyl ismethyl or ethyl; (1-3C)normal alkyl is methyl, ethyl or propyl;(1-4C)alkyl is methyl, ethyl, propyl, isopropyl, butyl, isobutyl, ort-butyl; (1-6C)alkyl is methyl, ethyl, propyl, butyl, pentyl or hexyl;(3-6C)cycloalkyl is cyclopropyl, cyclobutyl, cyclopenytyl or cyclohexyl.5. The compound of claim 4 wherein Q¹ is 5-chloropyridin-2-yl, or5-fluoropyridin-2-yl.
 6. The compound of claim 4 wherein R² is(1-isopropylpiperidin-4-ylcarbonyl)amino,(1-cyclohexylpiperidin-4-ylcarbonyl)amino,(4-isopropylpiperazin-1-ylcarbonyl)amino,[1-(tetrahydropyran-4-yl)piperidin-4-ylcarbonyl]amino,[4-(1-pyrrolidinyl)piperidin-1-ylcarbonyl]amino,[1-(4-pyridinyl)piperidin-4-ylmethyl]amino,[1-(2-carboxypyridin-4-yl)piperidin-4-ylmethyl]amino, or[1-(2-methoxycarbonylpyridin-4-yl)piperidin-4-ylmethyl]amino.
 7. Thecompound as claimed in claim 4 wherein each of R³-R⁶ is hydrogen.
 8. Thecompound as claimed in claim 4 wherein each of R³, R⁴ and R⁶ is hydrogenand R⁵ is chloro or fluoro.
 9. The compound as claimed in claim 1wherein each of R³, R⁴ and R⁶ is hydrogen and R⁵ is R^(a) wherein R^(a)is phenyl, furanyl, thienyl, 2-isothiazolyl or pyridyl; and wherein halois fluoro, chloro, bromo or iodo; (1-2C)alkyl is methyl or ethyl;(1-3C)normal alkyl is methyl, ethyl or propyl; (1-4C)alkyl is methyl,ethyl, propyl, isopropyl, butyl, isobutyl, or t-butyl; (1-6C)alkyl ismethyl, ethyl, propyl, butyl, pentyl or hexyl; (3-6C)cycloalkyl iscyclopropyl, cyclobutyl, cyclopenytyl or cyclohexyl.
 10. Thepharmaceutically acceptable salt of a compound of formula I as claimedin any of claims 1-3 which is an acid-addition salt made from a basiccompound of formula I and an acid which provides a pharmaceuticallyacceptable anion or a salt which is made from an acidic compound offormula I and a base which provides a pharmaceutically acceptablecation.
 11. A pharmaceutical formulation comprising in association witha pharmaceutically acceptable carrier, diluent or excipient, a novelcompound of formula I (or a pharmaceutically acceptable salt thereof) asprovided in any of claims 1-3.
 12. A process for preparing a compound offormula I (or a pharmaceutically acceptable salt thereof) as provided inclaim 1 or 2 which is selected from (A) for a compound of formula I inwhich —L²—Q², is —NH—CO—Q², —NH—CO—X—Q², —NH—CO—O—X—Q² or—NH—CO—NH—X—Q², acylating an amine of formula II,

 using a corresponding acid of formula HO—CO—Q², HO—CO—X—Q²,HO—CO—O—X—Q², or HO—CO—NH—X—Q², or an activated derivative thereof; (B)for a compound of formula I in which —L²—Q² is —O—CH₂—Q^(2A), akylatinga phenol of formula III

 using a reagent of formula Y—CH₂—Q^(2A) in which Y is a conventionalleaving group; (C) acylating an amine of formula H₂N—Q¹, or adeprotonated derivative thereof, using an acid of formula IV, or anactivated derivative thereof;

(D) for a compound of formula I in which R² is —NH—CH₂—Q^(2A),alkylating an amine of formula II directly, using a compound of formulaY—CH₂—Q^(2A), or indirectly by reductive alkylation using an aldehyde offormula Q^(2A)—CHO; (E) for a compound of formula I in which R² is—NH—CO—O—X—Q^(2A), or —NH—CO—NH—X—Q^(2A), acylating an alcohol offormula HO—X—Q^(2A)or an amine of formula NH₂—X—Q^(2A), using anactivated derivative of an acid of formula VI;

(F) for a compound of formula I in which R² is —NH—CO—X—Q^(2B) in whichX is a single bond, acylating at the 1-position a piperazine of formulaH—Q^(2B), using an activated derivative of an acid of formula VI; (G)for a compound of formula I in which R² is —NH—CO—X—Q^(2B) in which X ismethylene, alkylating at the 1-position a piperazine of formulaH—Q^(2B), using an alkylating agent of formula VII

 in which Y is a leaving group; (H) for a compound of formula I in whichR^(2A) is methylsulfonyl, substituting the amino nitrogen of acorresponding compound of formula I in which R^(2A) is hydrogen using anactivated derivative of methanesulfonic acid; (I) for a compound offormula I in which R^(2A) is —CHR^(y)R^(z) or —CHR^(w)R^(x), alkylatingthe amino nitrogen of a corresponding compound of formula I in whichR^(2A) is hydrogen using an alkylating agent of formula Y—CHR^(y)R^(z)or Y—CHR^(w)R^(x) or reductively alkylating the amine using a compoundof formula R^(y)—CO—R^(z) or R^(w)—CO—R^(x); (J) for a compound offormula I in which R^(2A) is 4-pyridinyl (which is unsubstituted orbears a substituent R^(v) at the 2- or 3-position), substituting theamino nitrogen of a corresponding compound of formula I in which R^(2A)is hydrogen using a corresponding pyridine reagent bearing a leavinggroup Y at the 4-position; (K) for a compound of formula I in whichR^(2A) is 4-pyridinyl in which R^(v) is alkoxycarbonyl, esterifying acorresponding compound of formula I in which R^(v) is carboxy; (L) for acompound of formula I in which R^(2A) is 4-pyridinyl in which R^(v) ishydroxymethyl, reducing the ester of a corresponding compound of formulaI in which R^(v) is alkoxycarbonyl; (M) for a compound of formula I inwhich R^(2A) is 4-pyridinyl in which R^(v) is carbamoyl, amidating theester of a corresponding compound of formula I in which R^(v) isalkoxycarbonyl; (N) for a compound of formula I in which R^(2A) is4-pyridinyl in which R^(v) is thiocarbamoyl, adding H₂S to the nitrileof a corresponding compound of formula I in which R^(v) is cyano; (O)for a compound of formula I in which R^(2A) is 4-pyridinyl in whichR^(v) is N-hydroxyamidino, adding H₂NOH to the nitrile of acorresponding compound of formula I in which R^(v) is cyano; (P) for acompound of formula I in which R^(2A) is 4-pyridinyl in which R^(v) iscarboxy, decomposing the ester of a corresponding compound of formula Iin which R^(v) is alkoxycarbonyl; (Q) for a compound of formula I inwhich —NR^(s)R^(t) is other than amino, alkylating a correspondingcompound of formula I in which —NR^(s)R^(t) is amino using aconventional method; (R) for a compound of formula I which bears—NR^(s)R^(t), reductively alkylating H—NR^(s)R^(t) using a correspondingcompound but in which the carbon to bear the —NR^(s)R^(t) group bears anoxo group; (S) for a compound of formula I in which R^(p) is1-hydroxy-1-methylethyl, adding a methyl group to the carbonyl group ofa corresponding compound of formula I in which R^(p) is acetyl using anorganometallic reagent; (T) for a compound of formula I in which R^(p)is 1-methoxy-1-methylethyl, treating a corresponding compound of formulaI in which R^(p) is 1-hydroxy-1-methylethyl with methanol and an acidcatalyst; (U) for a compound of formula I in which R⁴ or R⁵ is amino,reducing the nitro group of a compound corresponding to a compound offormula I but in which R⁴ or R⁵ is nitro; (V) for a compound of formulaI in which R⁴ or R⁵ is R^(g)NH— and R^(g) is R^(h)SO₂—, substituting theamino group of a corresponding compound of formula I in which R⁴ or R⁵is amino using an activated derivative of the sulfonic acid R^(h)SO₂—OH;whereafter, for any of the above procedures, when a functional group isprotected using a protecting group, removing the protecting group;whereafter, for any of the above procedures, when a pharmaceuticallyacceptable salt of a compound of formula I is required, it is obtainedby reacting the basic form of a basic compound of formula I with an acidaffording a physiologically acceptable counterion or the acidic form ofan acidic compound of formula I with a base affording a physiologicallyacceptable counterion or by any other conventional procedure; andwherein, unless otherwise specified, A³-A⁶, L¹, Q¹ and R² have any ofthe values defined in claim 1 or
 2. 13. A method of inhibiting factor Xain a mammal comprising administering to the mammal in need thereof, aneffective amount of a compound of formula I as provided in any of claims1-3.
 14. The compound of claim 5 wherein R² is(1-isopropylpiperidin-4-ylcarbonyl)amino,(1-cyclohexylpiperidin-4-ylcarbonyl)amino,(4-isopropylpiperazin-1-ylcarbonyl)amino,[1-(tetrahydropyran-4-yl)piperidin-4-ylcarbonyl]amino,[4-(1-pyrrolidinyl)piperidin-1-ylcarbonyl]amino,[1-(4-pyridinyl)piperidin-4-ylmethyl]amino,[1-(2-carboxypyridin-4-yl)piperidin-4-ylmethyl]amino, or[1-(2-methoxycarbonylpyridin-4-yl)piperidin-4-ylmethyl]amino.
 15. Thecompound as claimed in claim 5 wherein each of R³-R⁶ is hydrogen. 16.The compound as claimed in claim 6 wherein each of R³-R⁶ is hydrogen.17. The compound as claimed in claim 14 wherein each of R³-R⁶ ishydrogen.
 18. The compound as claimed in claim 5 wherein each of R³, R⁴and R⁶ is hydrogen and R⁵ is chloro or fluoro.
 19. The compound asclaimed in claim 6 wherein each of R³, R⁴ and R⁶ is hydrogen and R⁵ ischloro or fluoro.
 20. The compound as claimed in claim 14 wherein eachof R³, R⁴ and R⁶ is hydrogen and R⁵ is chloro or fluoro.
 21. Thecompound of claim 9 wherein Q¹ is 5-chloropyridin-2-yl, or5-fluoropyridin-2-yl.
 22. The compound of claim 9 wherein R² is(1-isopropylpiperidin-4-ylcarbonyl)amino,(1-cyclohexylpiperidin-4-ylcarbonyl)amino,(4-isopropylpiperazin-1-ylcarbonyl)amino,[1-(tetrahydropyran-4-yl)piperidin-4-ylcarbonyl]amino,[4-(1-pyrrolidinyl)piperidin-1-ylcarbonyl]amino,[1-(4-pyridinyl)piperidin-4-ylmethyl]amino,[1-(2-carboxypyridin-4-yl)piperidin-4-ylmethyl]amino, or[1-(2-methoxycarbonylpyridin-4-yl)piperidin-4-ylmethyl]amino.
 23. Thecompound of claim 21 wherein R² is(1-isopropylpiperidin-4-ylcarbonyl)amino,(1-cyclohexylpiperidin-4-ylcarbonyl)amino,(4-isopropylpiperazin-1-ylcarbonyl)amino,[1-(tetrahydropyran-4-yl)piperidin-4-ylcarbonyl]amino,[4-(1-pyrrolidinyl)piperidin-1-ylcarbonyl]amino,[1-(4-pyridinyl)piperidin-4-ylmethyl]amino,[1-(2-carboxypyridin-4-yl)piperidin-4-ylmethyl]amino, or[1-(2-methoxycarbonylpyridin-4-yl)piperidin-4-ylmethyl]amino. 24.5-Chloro-N-(5-chloropyridin-2-yl)-2-[(1-isopropylpiperidin-4-ylcarbonyl)amino]benzamide,or a pharmaceutically acceptable salt thereof.